NIH Director's New Innovator Award Recipients
Bassem Al-Sady, Ph.D.University of California at San Francisco
Project Title: Reconstructing Dynamic Epigenetic Genome Partitioning in Single Stem Cells
Grant ID: DP2-GM-123484
Bassem Al-Sady is from Nuernberg, Germany and received his Masters’ in Biochemistry from the University of Oxford in the United Kingdom. Bassem earned his Ph.D. in Plant Biology from the University of California at Berkeley where he worked with Dr. Peter Quail on the primary mechanism by which the plant photoreceptor phytochrome rapidly transmits light signals to the cell nucleus. Following completion of his Ph.D., he received his postdoctoral training with Drs. Geeta Narlikar and Hiten Madhani in the Department of Biochemistry and Biophysics at the University of California, San Francisco (UCSF). In his postdoctoral work, Bassem focused on unraveling biochemical principles of heterochromatin assembly, as well as the mechanisms of propagation of heterochromatin information along the chromosome using the fission yeast model. In 2013, he joined the faculty in the Department of Microbiology and Immunology at UCSF as Assistant Professor in Residence, where his group builds biochemical and single cell genetic tools to dissect mechanisms of the heterochromatin spreading reaction in genome partitioning and directing differentiation.
Jason R. Andrews, M.D., S.M.Stanford University
Project Title: Congregate Air Sampling for Population-Based Detection of Tuberculosis
Grant ID: DP2-AI-131082
Jason Andrews is an Assistant Professor of Medicine in the Division of Infectious Diseases and Geographic Medicine at Stanford University and a practicing infectious diseases physician. A graduate of Yale College, Yale School of Medicine and Harvard School of Public Health, his research focuses on developing and evaluating novel methods for diagnosis and understanding transmission dynamics of tuberculosis and tropical diseases. His work includes field sites in South Africa, Brazil and Nepal, and incorporates field and molecular epidemiology, microbiology, statistical inference, and mathematical modeling.
Effie Apostolou, Ph.D.Weill Cornell Medicine
Project Title: Defining the Role of Chromatin Architecture in Cell Fate Inheritance
Grant ID: DP2-DA-043813
Effie Apostolou is an Assistant Professor of Molecular Biology in Medicine at the Department of Medicine and the Meyer Cancer Center at Weill Cornell Medicine in New York. Her research focus is to understand the interplay between transcription factors and higher-order chromatin organization in the regulation of gene expression and cell identity. She received her B.Sc. in Biology from the Aristotle University of Thessaloniki and her Ph.D in Molecular Biology from the National University of Athens in Greece. As a PhD student in Dimitris Thanos’ lab in Athens, Greece, she discovered novel molecular mechanisms that drive stochastic gene expression upon viral infection. For her postdoctoral studies, she joined Konrad Hochedlinger’s lab at the Massachussetts General Hospital and Harvard Stem Cell Institute, Boston, where she focused on dissecting epigenetic and chromatin organization changes during somatic cell reprogramming and their effect on pluripotency. Effie is also a recipient of an Edward Jr Mallinckrodt research grant and of two Tri-Institutional Stem cell Initiative Grants funded by the Starr Foundation.
Daniel E. Bauer, M.D., Ph.D.Harvard Medical School and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Project Title: High-Throughput Discovery of Essential Noncoding Sequences for Erythropoiesis
Grant ID: DP2-HL-137300
Daniel Bauer is an assistant professor in pediatrics at Harvard Medical School and staff physician at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. His research program integrates genetic, epigenetic, and functional genomic methodologies to understand the determinants of blood cell development and develop innovative therapeutic strategies for blood disorders. He received his ScB in Biology from Brown University and MD/PhD from the University of Pennsylvania where his graduate work in the lab of Craig Thompson focused on the role of glucose metabolism and lipid biosynthesis in the growth of normal and malignant hematopoietic cells. Following clinical training in pediatrics and pediatric hematology/oncology at Boston Children’s Hospital and Dana-Farber Cancer Institute, he performed post-doctoral work in Stuart Orkin’s lab where he identified an erythroid enhancer element of the BCL11A gene that is a critical regulator of fetal hemoglobin level and a potential therapeutic target for the β-hemoglobin disorders. He is the recipient of awards from the American Society of Hematology, Burroughs Wellcome Fund, and Doris Duke Charitable, Charles H. Hood and Cooley’s Anemia Foundations.
Sean Bendall, Ph.D.Stanford University, School of Medicine
Project Title: Origins of Human Blood Lineages in Regenerative Medicine
Grant ID: DP2-EB-024246
Sean is currently an Assistant Professor in the Department of Pathology at Stanford University School of Medicine. Sean completed his B.Sc. in Biochemistry with a specialization in mass spectrometry-based proteomics at the University of Victoria, Canada. He went onto a Ph.D. in the Department of Biochemistry at the University of Western Ontario, Canada where his thesis work focused on the identification of intrinsic and extrinsic regulators of the human embryonic stem cell state with Mick Bhatia & Gilles Lajoie. Sean came to Stanford as a CIHR and Damon Runyon postdoctoral fellow with Garry Nolan where he developed new single cell proteomic technologies for analysis of the human hematopoietic immune system. Now, his lab continues to push the boundaries on single cell analysis and subcellular imaging, addressing questions in problems surounding human immunology, regenerative medicine, and stem cell biology.
Parijat Bhatnagar, Ph.D.SRI International
Project Title: Self-Assembled Therapeutics with Spatiotemporal Resolution
Grant ID: DP2-EB-024245
Parijat Bhatnagar is the Program Director for Cell-based Medicine in the Biosciences Division at SRI International. His research is in developing cellular therapeutics that can actively seek disease microenvironments, assess the disease burden, and synthesize proportionate amounts of therapeutic peptides upon engaging the molecular antigens on disease cells. He is also developing technologies for scaling up the manufacturing of these therapeutic cells. His post-doctoral training was in T-cell engineering at MD Anderson Cancer Center with a joint position at Houston Methodist Research Institute, where he developed approaches for imaging adoptively transferred T cells. He holds a PhD in Biomedical Engineering from Cornell University. His thesis was on microfabrication of photoactivatable biomaterials and micro-electro-mechanical systems.
Stephen Brohawn, Ph.D.University of California, Berkeley
Project Title: New Approaches to Understanding Biological Force Sensation
Grant ID: DP2-GM-123496
Stephen Brohawn received his B.S. in Biochemistry from the University of Delaware in 2004. In 2010, he received his Ph.D. in Biology from the Massachusetts Institute of Technology after conducting his thesis work in the laboratory of Thomas Schwartz where he studied the structure and function of the nuclear pore complex. He then joined Dr. Roderick MacKinnon’s laboratory at the Rockefeller University as a postdoctoral fellow of the Helen Hay Whitney Foundation where he characterized the physical, mechanistic and cellular basis of ion channels that sense mechanical force. Stephen is currently an Assistant Professor in the Department of Molecular & Cellular Biology and the Helen Wills Neuroscience Institute at the University of California, Berkeley where his lab studies molecular and cellular principles of electrical signaling and sensory transduction. Stephen is also a Klingenstein-Simons Neuroscience Fellow.
Irene A. Chen, M.D., Ph.D.University of California, Santa Barbara
Project Title: Understanding How Bacteriophages Affect Wound Ecologies and Developing New Tools to Harness Bacteria-Phage Interactions
Grant ID: DP2-GM-123457
Funded by the National Institute of General Medical Sciences
Irene Chen is an assistant professor in the Department of Chemistry and Biochemistry at UCSB. She received an A.B. in Chemistry, M.D., and Ph.D. in Biophysics from Harvard University. As a graduate student she worked with Jack Szostak to build simple cells and understand their emergent properties. She then joined the Bauer Fellows Program in systems biology at Harvard, where she studied RNA replication and evolution related to the origin of life. She began her lab at UCSB in 2013, where her group continues to study RNA evolution and has recently begun to study bacteriophages and their possible applications.
Isaac Chiu, Ph.D.Harvard Medical School
Project Title: Sensory Neuron-Bacteria Interactions in Modulating Pain and the Host Microbiota
Grant ID: DP2-AT-009499
Isaac Chiu is an assistant professor in the Department of Microbiology and Immunobiology at Harvard Medical School. He graduated with an A.B. in Biochemistry in 2002 from Harvard College, having worked through his undergraduate years in Professor Jack Strominger’s laboratory on the intracellular trafficking of immune molecules. He received his Ph.D. in Immunology in 2009 from Harvard Medical School under the guidance of Prof. Michael Carroll, where he worked on the role of microglia in Amyotrophic Lateral Sclerosis (ALS), and continued this work on neuro-inflammation as a postdoctoral fellow in Prof. Tom Maniatis’s laboratory. He then trained as a research fellow on the Neurobiology of Pain in Prof. Clifford Woolf’s laboratory at Boston Children’s Hospital. Dr. Chiu and his laboratory aims to understand how symbiotic and pathobiotic bacteria within the commensal microbiota interface with the sensory nervous system to modulate pain and inflammation.
Kwanghun Chung, Ph.D.Massachusetts Institute of Technology
Project Title: Proteome-Driven Holistic Reconstruction of Organ-Wide Multi-Scale Networks
Grant ID: DP2-ES-027992
Kwanghun Chung is currently the Samuel A. Goldblith Career Development Assistant Professor of Chemical Engineering at MIT, as well as a Core Member of the Institute for Medical Engineering and Science (IMES). He is also a Core Member of the Picower Institute for Learning and Memory, and an Associate Member of the Broad Institute. He received his B.S. in Chemical Engineering from Seoul National University in 2005, and then moved to Georgia Institute of Technology for his Ph.D. training under the mentorship of Dr. Hang Lu, where he developed automated and integrated microsystems for high-throughput imaging, molecular/behavioral phenotyping, and cell microsurgery of a broad range of living systems. Following his graduation in 2009, Dr. Chung joined the Karl Deisseroth Lab at Stanford University for post-doctoral training in 2010, where he invented a novel technology termed CLARITY, which enables system-wide structural and molecular analysis of large-scale intact biological samples. In 2013, Dr. Chung established his independent group at MIT and has been leading an interdisciplinary team to develop and apply novel technologies for holistic understanding of large-scale complex biological systems. Chung was the recipient of the Mcknight Technological Innovations in Neuroscience Award 2016, the Packard Fellowships for Science and Engineering Award 2015, the NARSAD Young Investigator Award 2015, the Yumin Awards for Creativity 2014, the Searle Scholars Award 2014, and the BWF Career Award at the Scientific Interface 2012.
Forrest W. Crawford, Ph.D.Yale School of Public Health
Project Title: Network-Based Epidemiology for Hidden and Hard-to-Reach Populations
Grant ID: DP2-HD-091799
Funded by the Big Data to Knowledge initiative
Forrest W. Crawford PhD received his BA in Neuroscience from Oberlin College, and his PhD in Biomathematics from the University of California Los Angeles. He is currently Assistant Professor in the Department of Biostatistics, Yale School of Public Health and Department of Ecology & Evolutionary Biology, Yale University. He is affiliated with the Center for Interdisciplinary Research on AIDS, the Yale Institute for Network Science, the Yale Computational Biology and Bioinformatics program, and the Operations doctoral program at the Yale School of Management. His research interests include networks, graphs, stochastic processes, and optimization, with applications in epidemiology, public health, and social science.
Alia Crum, Ph.D.Stanford University
Project Title: Harnessing Mindset in 21st Century Healthcare
Grant ID: DP2-AT-009511
Dr. Alia Crum is an Assistant Professor of Psychology at Stanford University. She received her PhD in Psychology from Yale University where she worked with Dr. Peter Salovey and Dr. Kelly Brownell. Inspired by research on the placebo effect, Dr. Crum’s research was the first to reveal the physiological effects of mindset in core areas of behavioral health including the benefits of exercise, the metabolic processing of nutrients, and the effects of stress. Dr. Crum’s research helps move us beyond the limited notion of the placebo effect as a mysterious response to an inert substance toward the recognition that ultimately our beliefs and expectations are responsible for physiological responses. As the director of the Mind & Body Lab and the health director at Stanford SPARQ (Social Psychological Answers to Real-world Questions), Dr. Crum leads a team of researchers aiming to better define the role social and psychological forces play in overcoming chronic disease with the goal of empowering individuals and health-care practitioners to harness these forces in the prevention and treatment of our most difficult public health challenges.
Monica Dus, Ph.D.The University of Michigan
Project Title: The Role of Neuroepigenetics in Bidirectional Behavioral States
Grant ID: DP2-DK-113750
Monica Dus joined the faculty of the Department of Molecular, Cellular, and Developmental Biology at The University of Michigan, Ann Arbor as an assistant professor and head of the Dus lab in 2015. She received a Ph.D. in Biology from the Watson School of Biological Sciences at Cold Spring Harbor Laboratory, where she studied the role of small noncoding RNAs in transposon control and genome stability with Dr. Gregory Hannon. Her postdoctoral work at the Skirball Institute of Biomolecular Medicine at the NYU School of Medicine uncovered how brain circuits sense nutrients to drive feeding decisions. At the University of Michigan the Dus lab studies how the environment, especially diet, leads to persistent changes in behavior by regulating the expression of genetic information within neurons through neuroepigenetic mechanisms. In addition to the NIH Director’s New Innovator Award, Dr. Dus received a NIH Pathway to Independence Award and the Klingenstein-Simons Fellowship Award in the Neurosciences; she is also a Rita Allen Milton Cassel Scholar and a NARSAD Young Investigator.
Elizabeth S. Egan, M.D., Ph.D.Stanford University School of Medicine
Project Title: Identifying Critical Erythrocyte Host Factors for Plasmodium falciparum Malaria
Grant ID: DP2-HL-137186
Elizabeth S. Egan received her B.A. from Barnard College of Columbia University after which she spent 18 months working in William Talbot’s laboratory studying pattern formation in zebrafish. She received her M.D./Ph.D. from Tufts University School of Medicine. As a graduate student working with Matthew Waldor she investigated the genetic determinants and dynamics of multi-chromosome replication in Vibrio cholerae. After her clinical training at Boston Children’s Hospital, she joined Manoj Duraisingh’s laboratory at Harvard School of Public Health through the Pediatric Scientist Development Program. During her postdoc she developed a forward genetic screen to identify host factors for Plasmodium falciparum malaria. Dr. Egan became an Assistant Professor in the Department of Pediatrics at Stanford in 2015, where her work focuses on understanding host erythrocyte determinants of malaria infection.
Polly Fordyce, Ph.D.Stanford University
Project Title: Leveraging Spectral Encoding for High Dimensional Biological Multiplexing
Grant ID: DP2-GM-123641
Polly Fordyce is an Assistant Professor in the Departments of Genetics and Bioengineering and the ChEM-H Institute at Stanford University. She received undergraduate degrees in Physics and Biology from the University of Colorado at Boulder before moving to Stanford University, where she earned a Ph.D. in Physics for work in Steve Block’s laboratory developing new single-molecule instrumentation and assays. For her postdoctoral research, she joined Joe DeRisi’s laboratory at UCSF, where she developed and applied new microfluidic tools for understanding transcription factor target specificity. In 2014, she launched her independent laboratory at Stanford University, where she and her team focus on developing new microfluidic technologies for high-throughput biophysical characterization of molecular interactions. She is the recipient of a Helen Hay Whitney Fellowship, a McCormick and Gabilan Fellowship, and a Pathway to Independence Award from the NIH.
Eric Lieberman Greer, Ph.D.Harvard Medical School and Boston Children’s Hospital
Project Title: Characterization of DNA N6-Methyl Adenine and Its Role in Epigenetic Memory
Grant ID: DP2-AG-055947
Eric Greer graduated from Case Western Reserve University with a B.A. in Biochemistry, and from Stanford Medical School with a Ph.D. in Cancer Biology from Anne Brunet’s lab. As a graduate student Eric identified molecular mechanisms that regulate longevity and showed that longevity could be transmitted in a non-genetic manner to descendants. As a post-doc in Yang Shi’s lab at Harvard Medical School he studied the mechanisms of transgenerational epigenetic inheritance. He identified methylation on the N6 position of adenines in DNA (6mA), a modification that was previously thought to be restricted to single celled organisms, as a new epigenetic modification in metazoa that might play a role in the inheritance of non-genetic information. The Greer lab at Boston Children’s Hospital and Harvard Medical School is studying the role of 6mA on gene expression and inheritance of epigenetic information. They are also interested in understanding the crosstalk between DNA methylation and histone modifications and how it influences chromatin accessibility in germ cells and somatic cells.
Shangqin Guo, Ph.D.Yale University
Project Title: Molecular Definition of Cancer Cell-of-Origin
Grant ID: DP2-GM-123507
Shangqin Guo is an Assistant Professor in the Department of Cell Biology and Yale Stem Cell Center. She received her B.S. from Sichuan University, Chengdu, China, and Ph.D. from Boston University School of Medicine. She studied hematopoietic stem and progenitor cell biology during her postdoctoral training in the laboratory of Dr. David Scadden. The Guo lab strives to understand the rules of cell fate determination. She is the recipient of Stem Cells Young Investigator Award in 2014, Gilead Sciences Research Scholar in Hematology/Oncology in 2015, and Charles H. Hood Foundation Child Health Research Award in 2016.
Sue Hammoud, Ph.D.University of Michigan
Project Title: Contributions of Sperm Chromatin to Development: A Myth or Reality?
Grant ID: DP2-HD-091949
Sue Hammoud is an Assistant Professor at University of Michigan in the Department of Human Genetics. Dr. Hammoud received her Ph.D. at the University of Utah. As a graduate student working with Drs. Brad Cairns and Douglas Carrell, Sue demonstrated that the paternal contribution to the embryo extends far beyond paternally imprinted genes and the genomic DNA sequence in sperm – encompassing histone modifications and small RNAs. As a postdoctoral Helen Hay Whitney fellow in the Cairns and Jones lab at the Huntsman Cancer Institute she has explored how chromatin regulates germline stem cell development and tissue homeostasis. Currently, Dr. Hammoud’s lab is investigating the cellular and genetic factors required to make a healthy and developmentally competent gamete.
Jesse V. Jokerst, Ph.D.University of California, San Diego
Project Title: Therapeutic Drug Monitoring with a Wearable Ultrasound-Based Sensor
Grant ID: DP2-HL-137187
Jesse Jokerst received a B.S. in chemistry from Truman State University (Kirksville, Missouri) and a Ph.D. in chemistry from The University of Texas at Austin in 2009 with John T. McDevitt. Jesse then completed postdoctoral training with Sanjiv Sam Gambhir at Stanford University Department of Radiology where he developed novel ultrasound and photoacoustic molecular imaging approaches to study ovarian cancer and monitor stem cell therapy. His current research emphasizes novel nanoparticle probes as acoustic contrast agents including hybrid imaging approaches utilizing wearable technologies. Jesse joined the Department of NanoEngineering at UC San Diego as an Assistant Professor in 2015 and is the previous recipient of the American Cancer Society Postdoctoral Fellowship and the NIH Pathway to Independence Award.
Ahmad S. Khalil, Ph.D.Boston University
Project Title: Combatting Antibiotic Resistance with Synthetic Biology Technologies
Grant ID: DP2-AI-131083
Ahmad (Mo) Khalil is an Assistant Professor of Biomedical Engineering, and Associate Director and Founding Member of the Biological Design Center at Boston University. He is also a Visiting Scholar at the Wyss Institute for Biologically Inspired Engineering at Harvard University. His laboratory is interested in how genetic networks give rise to complex cellular behaviors, and they develop synthetic biology approaches to study and control these cellular systems. Mo was an HHMI Postdoctoral Fellow with Dr. James Collins at Boston University. He completed his Ph.D. with Dr. Angela Belcher at MIT. He graduated Phi Beta Kappa from Stanford University with a B.S. in Mechanical Engineering and a minor in Chemistry.
Sebastian Klinge, Ph.D.The Rockefeller University
Project Title: Trapping and Reconstituting Early Stages of Eukaryotic Ribosome Assembly
Grant ID: DP2-GM-123459
Funded by the National Institute of General Medical Sciences
Sebastian Klinge received his Ph.D. in biochemistry from the University of Cambridge in 2009. As a postdoc he studied eukaryotic protein synthesis by X-ray crystallography and determined the first atomic structure of the large eukaryotic ribosomal subunit. Since 2013, he is an Assistant Professor and Head of the Laboratory of Protein and Nucleic Acid Chemistry at The Rockefeller University. His laboratory combines genetic, biochemical and structural biology techniques to elucidate the mechanisms of eukaryotic ribosome assembly in yeast.
Amnon Koren, Ph.D.Cornell University
Project Title: Personal Mutational Landscapes Encoded in Our DNA
Grant ID: DP2-GM-123495
Amnon Koren is an Assistant Professor and a Nancy and Peter Meinig Family Investigator in the Department of Molecular Biology and Genetics at Cornell University. He received his B.Sc. and M.A. from Tel-Aviv University, and his Ph.D. from The Weizmann Institute of Science under the guidance of Naama Barkai. He did his postdoctoral work with Judith Berman at the University of Minnesota, and with Steven McCarroll at Harvard Medical School and The Broad Institute. His research uses experimental and computational approaches to study the genomic regulation of DNA replication timing. In particular, his lab is utilizing human genetic variation to understand the molecular basis of DNA replication timing and its consequences for gene regulation, genome stability, and human phenotypes.
Joel Kralj, Ph.D.University of Colorado – Boulder
Project Title: Neuronal Electromics in Health and Disease
Grant ID: DP2-GM-123458
Joel Kralj received his BS in Engineering Physics from Santa Clara University, followed by a PhD in physics at Boston University. His graduate studies focused on understanding the molecular motions underlying light induced proton pumping in rhodopsins with Prof Kenneth Rothschild. His postdoctoral research was performed with Prof Adam Cohen in the Harvard Chemistry and Chemical Biology department. With Prof Cohen, Joel created a new class of genetically encoded fluorescent sensors capable of optically measuring voltage in single cells. In his own lab in the BioFrontiers Institute and MCD Biology Department at CU-Boulder, Dr. Kralj is broadly interested in uncovering genome wide influences on cellular voltage in a variety of model systems.
Anshul Kundaje, Ph.D.Stanford University
Project Title: Deep Learning Frameworks for Regulatory Genomics
Grant ID: DP2-GM-123485
Funded by the Big Data to Knowledge initiative
Anshul Kundaje is an Assistant Professor of Genetics and Computer Science at Stanford University. His research focuses on deciphering the molecular and genetic basis of disease by integrative analysis of diverse types of large-scale genomic data. The Kundaje lab develops statistical and machine learning methods to decipher functional elements in the human genome, understand their role in gene regulation and cellular function across diverse cell types and interpret the molecular and phenotypic impact of natural and disease-associated genetic variation. Anshul received a PhD. in Computer Science in 2008 from Columbia University. As a postdoctoral fellow at Stanford University from 2012-2014 and a research scientist at MIT and the Broad Institute from 2012-2014, he led the integrative analysis efforts for two of the largest functional genomics consortia - The Encyclopedia of DNA Elements (ENCODE) and The Roadmap Epigenomics Project.
Gabe Kwong, Ph.D.Georgia Tech and Emory
Project Title: Noninvasive and Predictive Biomarkers of Organ Transplant Rejection
Grant ID: DP2-HD-091793
Dr. Gabe Kwong joined the Department of Biomedical Engineering at Georgia Tech and Emory School of Medicine as an Assistant Professor in 2014. His research program is directed towards the advancement of human health by developing biomedical technologies that draw from the fields of Engineering and Immunology. He earned his B.S. in Bioengineering with Highest Honors from UC Berkeley, his Ph.D. from Caltech with Professor James R. Heath, and conducted postdoctoral work at MIT with Professor Sangeeta N. Bhatia. In recognition of his work, Dr. Kwong was named a “Future Leader in Cancer Research and Translational Medicine” by the Massachusetts General Hospital, and is the recipient of the NIH Ruth L. Kirschstein National Research Service Award, Burroughs Wellcome Fund Career Award at the Scientific Interface, and the NIH Director’s New Innovator Award. Dr. Kwong holds eight issued or pending patents, and has launched one biotechnology startup company.
Arthur Laganowsky, Ph.D.Texas A&M University
Project Title: Native Ion Mobility Mass Spectrometry Studies of Potassium Inward Rectifier Channels: Insight into Gating and Lipid Binding
Grant ID: DP2-GM-123486
Funded by the National Institute of General Medical Sciences
Arthur Laganowsky is an Assistant Professor at Texas A&M University. His laboratory focuses on membrane protein-lipid interactions, and how these interactions influence membrane protein structure and function. He received the Biochemistry Distinguished Dissertation Award for his doctoral work on structural studies of amyloid-related proteins in the laboratory of David Eisenberg at University of California Los Angeles. His postdoctoral work focused on ion mobility mass spectrometry of intact membrane protein complexes in the laboratory of Dame Carol V. Robinson at the University Oxford, and became a Nicholas Kurti Junior Research Fellow of Brasenose College.
Cecília Leal, Ph.D.University of Illinois at Urbana-Champaign
Project Title: A New Paradigm In Nanomedicine: Can Structural Interiors of Nanoparticles Regulate Cellular Delivery?
Grant ID: DP2-EB-024377
Cecília Leal is an Assistant Professor in the Department of Materials Science and Engineering and the Frederick Seitz Materials Research Laboratory at the University of Illinois, Urbana-Champaign since 2012. She graduated in Industrial Chemistry from Coimbra University in Portugal. Cecília moved to Sweden to receive her Ph.D. in physical chemistry from Lund University, supervised by Prof. Wennerström. After working for a year in the Norwegian Radium Hospital, she joined Prof. Safinya’s Lab at the University of California in Santa Barbara as a Vetenskapsrådet postdoctoral fellow. Her research interests focus on the characterization and functionalization of lipid materials for cellular delivery. In addition to the New Innovator award, she received the National Science Foundation CAREER award in 2016.
Meena S. Madhur, M.D., Ph.D.Vanderbilt University
Project Title: Immunophenotyping of Human Hypertension Using Single Cell Multiplex Mass Cytometry to Identify Novel Therapeutic Targets
Grant ID: DP2-HL-137166
Meena Madhur received her B.S. in Biomedical Engineering and Biology from Duke University followed by M.D./Ph.D degrees from the University of Virginia. She then returned to Duke University for her internship and residency in Internal Medicine. In 2007, she joined the cardiology fellowship program at Emory University where, in the laboratory of Dr. David Harrison, she demonstrated for the first time that the newly discovered cytokine, interleukin 17 (IL-17), plays a critical role in hypertension and vascular dysfunction. In 2012, she began her tenure-track appointment as Assistant Professor of Medicine with a secondary appointment in the Department of Molecular Physiology and Biophysics at Vanderbilt University. Her lab currently investigates the role of the adaptive immune system and T cell derived cytokines such as IL-17, IL-21, and interferon gamma on hypertension and the associated renal and vascular dysfunction.
Nikhil U. Nair, Ph.D.Tufts University
Project Title: Metabolic Engineering in Humans: Altered Gut Microbes as a Therapeutic Platform
Grant ID: DP2-HD-091798
Nikhil U. Nair has been an assistant professor in the department of Chemical & Biological Engineering at Tufts University since 2013. He received his B.S. in Chemical & Biomolecular Engineering from Cornell University in 2003 and then went on obtain his Ph.D. in Chemical & Biomolecular Engineering from the University of Illinois in 2010 under the guidance of synthetic biologist Huimin Zhao. For his post-doctoral training he worked in Ann Hochschild’s lab in Microbiology and Immunobiology at Harvard Medical School to elucidate novel regulatory aspects of transcriptional elongation in bacteria. Research in the Nair lab (sites.tufts.edu/nairlab) is focused on altering various aspects of microbial physiology (such as gene regulation and metabolism) not only to engineer them for biomedical, biochemical, and bioenergy applications, but to also understand how they interact with each other and their environment.
Tien Peng, M.D.University of California San Francisco
Project Title: Defining the Resident Mesenchymal Stem Cell Niche and Function In Vivo
Grant ID: DP2-AG-056034
Tien Peng is an Assistant Professor in the Department of Medicine and Cardiovascular Research Institute at UC San Francisco. Tien received his M.D. from Johns Hopkins before training at Columbia University for his medicine residency and University of Pennsylvania for his pulmonary/critical care fellowship. He completed his postdoctoral fellowship in the Department of Cell and Developmental Biology at Penn with Ed Morrisey, where he defined cellular feedback loops critical to establishing the mesenchymal progenitor niche during embryonic development and postnatal maintenance. Tien established his own lab at UCSF in 2015, and his group is exploring the nexus between development and aging to build new framework in the study of tissue regeneration.
Rushika M. Perera, Ph.D.University of California, San Francisco
Project Title: Tracking Tumor Evolution through In Vivo Organelle Profiling
Grant ID: DP2-CA-216364
Rushika Perera received her B.S. from the University of Melbourne and completed her Ph.D. studies at the Ludwig Institute for Cancer Research and the University of Melbourne, Australia. She trained as a postdoctoral fellow at Yale University with Drs. Derek Toomre and Pietro De Camilli studying phosphoinositde mediated control of endocytosis, and at Massachusetts General Hospital / Harvard Medical School in the laboratory of Dr. Nabeel Bardeesy where she uncovered mechanisms of autophagy-lysosome regulation and metabolic reprogramming in pancreatic cancer. In September 2015, she joined the Department of Anatomy at the University of California, San Francisco as an Assistant Professor, where her lab uses in vivo disease models to understand how alterations in organelle composition and function contribute to cancer initiation and progression. Dr. Perera is currently the recipient of an American Association for Cancer Research (AACR)-Pancreatic Cancer Action Network Career Development Award, a Hirshberg Foundation for Pancreatic Cancer Research Grant and was selected as a 2015 AACR-NextGen Star.
Sabine Petry, Ph.D.Princeton University
Project Title: Building the Chromosome Segregation Machinery from Scratch
Grant ID: DP2-GM-123493
Funded by the National Institute of General Medical Sciences
Sabine Petry is an Assistant Professor in the Molecular Biology Department at Princeton University. Her research group investigates how the microtubule cytoskeleton builds cellular structures by combining high-resolution microscopy methods with structural studies. Sabine was trained as a biochemist and performed her thesis research with Dr. Venki Ramakrishnan at the MRC Laboratory of Molecular Biology (UK), where she studied how translation factors drive protein synthesis in the ribosome using X-ray crystallography. As a postdoctoral HHMI Fellow of the Life Science Research Foundation in Ron Vale’s lab at UCSF, Sabine pursued the study of a larger molecular entity, the mitotic spindle. In addition to the NIH Director’s New Innovator Award, Sabine is a recipient of the NIH Pathway to Independence Award, the Kimmel Scholar Award for Cancer Research, the Packard Fellowship for Science and Engineering, and the Pew Biomedical Scholars Award.
Jeremy Purvis, Ph.D.University of North Carolina at Chapel Hill
Project Title: Controlling Stem Cell Fate through Computational Modeling
Grant ID: DP2-HD-091800
Jeremy Purvis is an Assistant Professor of Genetics at the University of North Carolina at Chapel Hill and a member of the Lineberger Comprehensive Cancer Center. He received a Ph.D. in Computational Biology from the University of Pennsylvania where he developed computational models of cell signaling with Scott Diamond and Ravi Radhakrishnan. He completed his postdoctoral training at Harvard Medical School under the mentorship of Galit Lahav, where he studied the role of p53 dynamics in the DNA damage response. As an independent investigator, his group seeks to understand how individual cells make fate decisions and how groups of interacting cells give rise to emergent properties. Their work focuses primarily on early differentiation decisions in human embryonic stem cells and cell cycle arrest decisions in the context of cancer.
Dragana Rogulja, Ph.D.Harvard Medical School
Project Title: Mechanisms of Arousal Threshold and Sleep Homeostasis
Grant ID: DP2-AT-009498
Dragana Rogulja was born and grew up in Belgrade, Serbia. She joined the Department of Neurobiology at Harvard Medical School in 2013 as an Assistant Professor. Her Ph.D. is from Rutgers University where she studied morphogen gradients with Ken Irvine, and her postdoc was at Rockefeller University where she studied sleep and circadian biology with Mike Young. Her lab has established a novel approach to studying sleep states in Drosophila which they are using to understand how information flow in the brain changes between wakefulness and sleep.
Melanie A. Samuel, Ph.D.Baylor College of Medicine
Project Title: Synaptic Reprogramming of Adult Neurons
Grant ID: DP2-EY-027984
Melanie Samuel aims to decode the structural and molecular regulators of adult synaptic rewiring. She is currently an Assistant Professor of Neuroscience and CPRIT Scholar in the Huffington Center on Aging at Baylor College of Medicine. As a Barry M. Goldwater Scholar she earned three bachelor’s degrees from the University of Idaho (summa cum laude) and then completed her Ph.D. at Washington University studying neurotropic viral pathogenesis with Michael Diamond. As a postdoctoral fellow with Joshua Sanes at Harvard University she developed the retina as a model for synaptic aging. Her past awards include those from the Howard Hughes Medical Institute, the Damon Runyon Cancer Research Foundation, the Brain Research Foundation and a Pathway to Independence Award from the NIH. Dr. Samuel’s interdisciplinary research group leverages nanoscopic imaging technologies and high throughput in vivo molecular studies of single cells and their circuits in order to identify ways to repair neural networks.
Rahul Satija, Ph.D.New York Genome Center and New York University
Project Title: Learning the Metadata of the Cell with Single Cell Genomics
Grant ID: DP2-HG-009623
Funded by the Big Data to Knowledge initiative
Rahul Satija is a Core Faculty Member at the New York Genome Center, and an Assistant Professor of Biology at NYU. His research is directed towards understanding cellular decision-making using single cell genomics, with a particular focus on the development and function of the mammalian immune system. As a postdoc in Aviv Regev’s lab at the Broad Institute, he developed new methods to infer a cell’s spatial localization, subtype, and regulatory state based on its gene expression. He holds a BS in Biology and Music from Duke University, and obtained his PhD in Statistics from Oxford University as a Rhodes Scholar.
Tiffany Schmidt, Ph.D.Northwestern University
Project Title: Genetic Mapping of Visual Circuits
Grant ID: DP2-EY-027983
Tiffany Schmidt received her B.A. in Psychology and Biology from Luther College in 2006. She did her Ph.D. work in the lab of Dr. Paulo Kofuji at the University of Minnesota, where she identified diverse structural and physiological properties of the recently discovered melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). Dr. Schmidt then went on to do her postdoctoral work in the lab of Dr. Samer Hattar in the Department of Biology at Johns Hopkins University, where she defined behavioral roles for these newly discovered ipRGC subtypes. In 2014, she joined the faculty as an Assistant Professor in the Department of Neurobiology at Northwestern University, where her lab focuses on elucidating the neural circuits underlying light-driven behavior.
Nikolai Slavov, Ph.D.Northeastern University
Project Title: Ribosome-Mediated Translational Regulation during Stem Cell Differentiation
Grant ID: DP2-GM-123497
Nikolai Slavov received undergraduate education at MIT and pursued doctoral research in the Botstein laboratory at Princeton University, aiming to understand how cells coordinate growth rate, gene expression, and metabolism. During his postdoctoral research in the van Oudenaarden laboratory at MIT, he characterized trade-offs of aerobic glycolysis (also known as Warburg effect). Subsequently, he obtained direct evidence for ribosome heterogeneity in yeast and in mouse embryonic stem cells. His laboratory explores the functional roles of this ribosome heterogeneity and the regulation of protein synthesis in single cells.
William R. Stauffer, Ph.D.University of Pittsburgh
Project Title: Neural Correlates of Optimal Value Seeking in the Reward System
Grant ID: DP2-MH-113095
William Stauffer received his BS in neuroscience (2003) and PhD in bioengineering (2009) from the University of Pittsburgh. During his graduate studies in Tracy Cui’s lab he focused his research efforts on the neural tissue – electrode interface; his research developed methods to promote neural adhesion and to precisely deliver neuroactive chemicals to study information flow in a network. In 2009 he became a postdoc in Wolfram Schultz’s behavioral neuroscience laboratory at the University of Cambridge where he investigated neural coding of economic variables, and developed a technique to enable cell-type specific optogenetics in dopamine neurons of Rhesus macaque monkeys. William joined the faculty of the Department of Neurobiology at the University of Pittsburgh in 2015. During the past year, William has developed a multidisciplinary research program focused on: (1) investigating the behavioral functions of the reward system – from deliberation and decision making to learning and memory formation – and (2) developing enabling technologies to bridge the gap between molecular and systems neuroscience.
Matthew Steinhauser, M.D.Brigham and Women’s Hospital
Project Title: A New Modality to Image Tumor Metabolic Heterogeneity at Subcellular Resolution
Grant ID: DP2-CA-216362
Matthew Steinhauser received his undergraduate and medical degrees at the University of Michigan, where he studied the cytokine and chemokine networks that regulate acute and chronic inflammation in the laboratory of Dr. Steven Kunkel. He then completed clinical training in internal medicine at Columbia University Medical Center, followed by subspecialty training in cardiology at Brigham and Women’s Hospital. After post-doctoral training in stem cell biology and cardiac regeneration in the laboratory of Dr. Richard Lee, Dr. Steinhauser started an independent laboratory in the Division of Genetics at Brigham and Women’s Hospital. He studies the cellular and metabolic adaptation of adipose tissue to changes in caloric intake and how such responses influence cardiometabolic disease. More recently the laboratory has developed an interest in the metabolic adaptations undertaken by cancer cells to promote survival, growth, and resistance to targeted therapies.
Kelly R. Stevens, Ph.D.University of Washington
Project Title: Thermogenetic Activation of Engineered Tissue for Cardiac Repair
Grant ID: DP2-HL-137188
Funded by the National Heart, Lung, and Blood Institute
Kelly Stevens is an Assistant Professor in the Departments of Bioengineering and Pathology at the University of Washington. Her research focuses on developing new technologies to assemble artificial human tissues from stem cells, and then remotely control these tissues after implantation in a patient. Dr. Stevens received a B.S. in Biomedical Engineering from the University of Wisconsin-Madison, a Ph.D. in Bioengineering from the University of Washington, and postdoctoral training at Massachusetts Institute of Technology. Her scientific contributions to date have centered on the development of complex multicellular tissues for organ repair, with increasing focus on enhancing tissue function, microvascularization, and organization. Some examples include the construction of functional scaffold-free cardiac tissue from pluripotent stem cells, the subsequent ‘pre-vascularization’ of these tissues using the intrinsic capacity of microvascular cells to self-organize, and the geometric control of multicellular patterning for optimal cellular function and microvascular ingrowth after implantation.
Bozhi Tian, Ph.D.University of Chicago
Project Title: Silicon-Based Injectable Micro-gels for Non-genetic and Wireless Modulation of Neurons, Cardiomyocytes and Neuromuscular System
Grant ID: DP2-NS-101488
Bozhi Tian received his Ph.D. in physical chemistry from Harvard University, where he worked with Professor Charles Lieber on synthetic techniques for nanowire materials, fundamental study of high-performance nanowire photovoltaics, and development of advanced nanoelectronic devices for electrophysiology. He then worked as a postdoctoral scholar at MIT and Harvard Medical School with Professors Robert Langer and Daniel Kohane on tissue engineering and biomaterials development. He is currently an assistant professor at the University of Chicago, with research focusing on semiconductor-enabled exploration of cellular biophysics and soft matter dynamics. His lab has developed a class of silicon-based materials and devices that exhibit enhanced interactions with subcellular components, demonstrating applications in cellular force dynamics measurement and optical modulation of neurons. Dr. Tian’s accolades during his independent career include Presidential Early Career Awards for Scientists and Engineers (PECASE) (2016), ONR young investigator award (2016), Sloan fellowship (2016), AFOSR young investigator award (2015), NSF CAREER award (2013), Searle Scholar award (2013), and TR35 honoree (2012).
Jared Toettcher, Ph.D.Princeton University
Project Title: Harnessing Optogenetics to Diagnose and Therapeutically Rewire Cancer Cell Signaling
Grant ID: DP2-EB-024247
Jared Toettcher received his B.S. in Bioengineering from UC Berkeley and his Ph.D. in Biological Engineering from MIT, where he studied the relationship between mammalian cells’ surveillance of DNA damage and decision to undergo cell cycle arrest under the mentorship of Bruce Tidor (MIT) and Galit Lahav (Harvard Medical School). As a postdoctoral fellow in the laboratories of Wendell Lim and Orion Weiner at UCSF, Dr. Toettcher pioneered the use of precise optogenetic control to study signaling in the mammalian Ras and PI 3-kinase pathways. He is currently an Assistant Professor of Molecular Biology at Princeton University, where his lab primarily studies how growth factor signaling pathways process extracellular information to control diverse cellular responses. His current work spans model systems including the early fly embryo, mammalian tissues and tumor cells. Dr. Toettcher’s honors and awards include a Cancer Research Institute fellowship, an MIT Presidential Fellowship and a UC Berkeley Regents’ Scholarship.
Elçin Ünal, Ph.D.University of California, Berkeley
Project Title: Illuminating Cellular Aging Pathways through Gametogenesis
Grant ID: DP2-AG-055946
Elçin Ünal is an Assistant Professor in the Molecular and Cell Biology Department at the University of California, Berkeley. Her lab studies the principles that control the nuclear and cytoplasmic integrity of gametes towards understanding how gamete formation counteracts age-induced cellular damage and how the meiotic cells partition their chromosomes. Elçin received her undergraduate degree in Molecular Biology and Genetics from Bilkent University, Turkey. She then moved to the United States to pursue her PhD research in Doug Koshland’s lab at the Carnegie Institution, Department of Embryology and completed postdoctoral training in Angelika Amon’s lab at MIT. In addition to the NIH Innovator Award, Elçin is the recipient of a Pew Scholarship, a March of Dimes Basil O’Connor Award as well as a Damon Runyon Rachleff Innovator Award.
Elizabeth Villa, Ph.D.University of California San Diego
Project Title: Opening Windows into the Cell: Revealing the Molecular Architecture of the Nuclear Periphery
Grant ID: DP2-GM-123494
Funded by the National Institute of General Medical Sciences
Elizabeth Villa received a Ph.D. in Biophysics from the University of Illinois at Urbana-Champaign working with Klaus Schulten on multiscale simulations of biomolecular complexes, where she work closely with Joachim Frank developing computational tools for cryo-electron microscopy. She was a Marie Curie postdoctoral fellow in the lab of Wolfgang Baumeister at the Max Planck Institute of Biochemistry in Munich. Her lab develops tools to observe macromolecular complexes in their natural environment, the cell. Her goal is to transform cryo-electron tomography into a high-resolution technique to unveil the structural dynamics of these complexes that is directly compatible with other biophysics experiments. She combines cell biology and cryo-electron microscopy to generate data, and use computational analysis and physical modeling to understand these data. Her current research is focused on studying the nuclear periphery, one of the most exciting and structurally uncharted territories in the cell.
Arun P. Wiita, M.D., Ph.D.University of California, San Francisco School of Medicine
Project Title: In Vivo Monitoring of Oxidative Protein Folding through Time-Resolved Quantitative Mass Spectrometry
Grant ID: DP2-GM-123500
Arun Wiita completed his undergraduate training in Chemistry at Princeton University and a combined MD/PhD at Columbia University with graduate training in single molecule biophysics in the laboratory of Julio Fernandez. Dr. Wiita went on to UCSF to complete residency training in Laboratory Medicine (Clinical Pathology) and then joined the lab of Jim Wells at UCSF as a Damon Runyon Postdoctoral Fellow. In 2014, Dr. Wiita started his own lab at UCSF with a range of interests spanning basic and translational research in hematologic malignancies and genetic disease. The core goal of his group is answering unresolved clinical questions with advanced applications of quantitative mass spectrometry-based proteomics, with a particular focus on mechanisms linking cellular genomic aberrations to phenotypic changes mediated at the protein level.
Wen Xue, Ph.D.University of Massachusetts Medical School
Project Title: CRISPR-Based Modular Therapy for Precision Medicine
Grant ID: DP2-HL-137167
Dr. Wen Xue is an Assistant Professor in the RNA Therapeutics Institute at University of Massachusetts Medical School. His research focuses on building precision mouse models of cancer and genetic diseases using RNA tools. Dr. Xue received his B.S. and M.S. from Nanjing University, China. He did Ph.D. training with Dr. Scott Lowe at the Cold Spring Harbor labs and postdoctoral training under the mentorship of Dr. Tyler Jacks at MIT. In addition to the NIH Director’s New Innovator Award, his lab is supported by the NCI R00, NHLBI P01, American Cancer Society, Lung Cancer Research Foundation, and Hyundai Hope On Wheels Pediatric Cancer Grant.
Michael M. Yartsev, Ph.D.University of California, Berkeley
Project Title: The First Mammalian Model System for Studying Vocal Learning: A Behavioral and Neurophysiological Approach
Grant ID: DP2-DC-016163
Michael Yartsev received his Ph.D. at the Weizmann Institute where he worked in the laboratory of Nachum Ulanovsky on the neurobiological basis of multi-dimensional spatial representation in the hippocampal formation of freely behaving and flying bats. He then joined Princeton University and the laboratory of Carlos Brody as a CV Starr fellow where he studied the computations performed by striatal circuits during gradual accumulation of sensory evidence. He is currently an Assistant Professor of department of bioengineering and the Helen Wills neuroscience institute at UC Berkeley. His lab's goal is to use the bat in order to understand the detailed neurobiological computations that support complex spatial and acoustic behaviors in mammals. In addition to the NIH Director’s New Innovator Award, Dr. Yartsev is also a Searle Scholar, a PEW scholar, a Klingenstein-Simons Fellow, recipient of the Brain Initiative EAGER award from the National Science Foundation as well as recipient of the Human Frontiers Research Program Grant.
Mohamed S. Abou Donia, Ph.D.Princeton University
Project Title: Uncultivated Bacterial Symbionts of Humans: an Untapped Resource for Drug Discovery
Grant ID: DP2-AI-124441
Mohamed S. Abou Donia received his B.Sc. in Pharmacy from the Faculty of Pharmacy, Suez Canal University, Egypt in 2004, and his Ph.D. from the Medicinal Chemistry Department, School of Pharmacy, University of Utah in 2010. During his graduate studies, he worked in Dr. Eric Schmidt's laboratory where he studied the biosynthesis and genetic engineering of small molecules produced by uncultivated bacterial symbionts of marine invertebrates. In 2010, he joined Dr. Michael Fischbach's laboratory at the Department of Bioengineering and Therapeutic Sciences at the University of California, San Francisco as a postdoctoral scholar, where he studied small molecules produced by members of the human microbiome and their role in mediating microbe-host and microbe-microbe interactions in humans. In 2014, Mohamed joined the Princeton faculty at the Department of Molecular Biology, where he started a multidisciplinary research program to study the complex network of chemical and biological interactions mediated within complex microbiomes of humans and other animals, using a combination of computational, chemical, metagenomic, and microbiological approaches.
Alexander Barnes, Ph.D.Washington University in St. Louis
Project Title: High-Sensitivity NMR at Room Temperature for Molecular Structure and Dynamics
Grant ID: DP2-GM-119131
Alexander Barnes received his Ph.D. in Physical Chemistry from M.I.T., where he developed NMR instrumentation and signal enhancement methods in the laboratories of Robert Griffin and Richard Temkin. He conducted his post-doctoral research at Stanford University using solid state NMR to determine the structure of protein kinase C (PKC) activators with Lynette Cegelski and Paul Wender. Alexander’s laboratory develops novel magnetic resonance technology and methods to characterize biomolecular structure and molecular dynamics. Biomedical applications include the development of isozyme specific PKC activators, which are promising candidates to activate latent HIV reservoirs.
Artem Barski, Ph.D.Cincinnati Children’s Hospital Medical Center and University of Cincinnati
Project Title: Direct Epigenetic Reprogramming of T Cells
Grant ID: DP2-GM-119134
Artem Barski received his undergraduate degree in chemistry from Moscow State University in 2000. His Ph.D. work in the laboratory of Baruch Frenkel, D.M.D., Ph.D., at the University of Southern California focused on transcriptional regulation in osteoblasts. During his postdoctoral training at the laboratory of Keji Zhao, Ph.D., at NHLBI, Dr. Barski took part in developing ChIP-Seq, a revolutionary technique for studying epigenetic landscapes in a genome-wide manner. After receiving an NHLBI career transition award (K22), Dr. Barski joined the Divisions of Allergy & Immunology and of Human Genetics at Cincinnati Children’s Hospital Medical Center in 2011. His laboratory studies epigenomics of the immune system and develops biochemical and computational methods for the study of epigenetic and transcriptional regulation of gene expression.
Sanjay Basu, M.D., Ph.D.Stanford University
Project Title: Cohort Filtering Models to Identify Social Program Effects on Health Disparities
Grant ID: DP2-MD-010478
Sanjay Basu is an Assistant Professor in the Department of Medicine at Stanford University. He received his B.S. from MIT, M.Sc. from Oxford, and M.D./Ph.D. from Yale before completing Internal Medicine residency at UCSF. Dr. Basu is an epidemiologist currently focused on the construction, validation and application of dynamic multi-level epidemiological models to improve strategies for cardiovascular disease prevention and treatment.
Eric J. Bennett, Ph.D.University of California San Diego
Project Title: Manipulating Protein Homeostasis through Specialized Quality Control Ribosomes
Grant ID: DP2-GM-119132
Eric Bennett is an Assistant Professor in the section of Cell and Developmental Biology at the University of California, San Diego. His research group develops and utilizes quantitative proteomic strategies to investigate ubiquitin-dependent control mechanisms that regulate protein homeostasis. Dr. Bennett received his B.S. in Biochemistry from Boston College and his Ph.D. from Stanford University. His graduate work in Ron Kopito’s lab focused on the role of the ubiquitin-proteasome system in promoting the clearance of toxic protein aggregates. He joined Wade Harper’s research group at Harvard Medical School for his postdoctoral studies where he received a Damon Runyon Postdoctoral Fellowship. In collaboration with Steven Gygi’s lab at Harvard, he developed and applied systems-level proteomic approaches aimed at understanding both the breadth of ubiquitin-dependent regulation of proteome dynamics and the specific mechanisms employed to impart regulatory control over cellular systems. In addition to the NIH Director’s New Innovator Award, Dr. Bennett has received a Hellman Fellowship Award, the Kimmel Scholar Award from the Sidney Kimmel Foundation for Cancer Research, and a New Scholar Award in Aging from the Ellison Medical Foundation.
Brenda L. Bloodgood, Ph.D.University of California, San Diego
Project Title: Charting a New Path for Rapid Signaling from the Synapse to the Nucleus
Grant ID: DP2-NS-097029
Brenda Bloodgood is an Assistant Professor at UC San Diego in the Division of Biological Sciences in the Neurobiology Section. Dr. Bloodgood graduated from UC San Diego in 2001 with a B.S. in Animal Physiology and Neuroscience and received her Ph.D. in Neurobiology from Harvard Medical School in 2006. As a graduate student working with Bernardo Sabatini she investigated the role of dendritic spines in shaping synaptic signals. Dr. Bloodgood conducted her postdoctoral studies in Michael Greenberg’s laboratory at Harvard Medical School where she began exploring the role of inducible transcription factors in regulating inhibitory synapses. Currently Dr. Bloodgood’s lab is focused on understanding how the activity of a neuron is interpreted by the genome to orchestrate behaviorally relevant circuit plasticity.
Gloria A. Brar, Ph.D.University of California-Berkeley
Project Title: Dissecting the Roles of Pervasive Short ORFs in Meiosis
Grant ID: DP2-GM-119138
Funded by the National Institute of General Medical Sciences
Gloria Brar received her undergraduate degree in Molecular and Cell Biology from UC-Berkeley. She received her Ph.D. in Biology in Angelika Amon's lab at MIT, where she studied the regulation of meiotic chromosome cohesion and segregation. Gloria joined Jonathan Weissman’s lab at UCSF as an American Cancer Society postdoctoral fellow and used the new method of ribosome profiling to define the complex regulation of gene expression that underlies meiosis in budding yeast. She is currently an Assistant Professor of Molecular and Cell Biology at UC-Berkeley, where her lab studies the dynamic and non-canonical gene regulation that allows cells to complete the comprehensive cellular remodeling that accompanies meiosis. Towards this end, the Brar lab is investigating the roles of the thousands of short Open Reading Frames that are translated specifically in meiotic cells, specializations to the meiotic ribosome, and the functions of stress response pathways in meiotic differentiation and organelle remodeling.
Francesca Cole, Ph.D.University of Texas MD Anderson Cancer Center
Project Title: Mechanistic Derivation of Germ Line Mutation by Genome-Wide Mouse Tetrad Analysis
Grant ID: DP2-HD-087943
Francesca Cole received her B.A. from Hunter College of the City University of New York and her Ph.D. from Mount Sinai School of Medicine, where she studied muscle and midline development in the laboratory of Rob S. Krauss. She then pursued a postdoctoral fellowship in the laboratory of Maria Jasin at Memorial Sloan-Kettering Cancer Center. She was recruited to the Department of Epigenetics and Molecular Carcinogenesis at the University of Texas MD Anderson Cancer Center as an Assistant Professor in September of 2012. The Cole laboratory investigates mechanisms of homologous recombination and germ line mutation using mouse meiosis as a model system. In addition to the NIH Director’s New Innovator Award, she is a CPRIT Scholar in Cancer Research and an R. Lee Clark Fellow.
Sophie Dumont, Ph.D.University of California, San Francisco
Project Title: Rewiring Cellular Architecture to Probe Mechanical Signal Processing at Kinetochores
Grant ID: DP2-GM-119177
Sophie Dumont is from Québec, Canada. She received her B.A. in physics from Princeton University, and Ph.D. in biophysics from UC Berkeley where she probed the mechanics of individual biomolecules with Carlos Bustamante. She was a Junior Fellow at the Harvard Society of Fellows and postdoc at Harvard Medical School where she worked on the mechanics of cell division with Tim Mitchison. She started her lab at UCSF in 2012, and her group focuses on the self-organization and emergent mechanics that drive robust chromosome segregation.
Jessica Feldman, Ph.D.Stanford University
Project Title: Mechanisms Controlling Microtubule Organization during Cell Differentiation
Grant ID: DP2-GM-119136
Jessica Feldman received her undergraduate degree in Biology from Columbia University where she studied topics ranging from primate social behavior to axon guidance molecules. She obtained her Ph.D. working with Wallace Marshall at University of California, San Francisco where she studied the genetic regulation of centrosome structure, function, and positioning and the mechanisms dictating internal cellular organization using the unicellular alga Chlamydomonas. Jessica went on to characterize the role of the centrosome during epithelial polarization in C. elegans, working as a postdoctoral fellow with Jim Priess at the Fred Hutchinson Cancer Research Center. Jessica started her own lab in the Biology Department at Stanford University in 2013, where her group studies structural changes that occur at the cellular level during normal development and in disease. In particular, her lab is interested in understanding how microtubules become spatially organized in different cell types during cell differentiation.
Liang Feng, Ph.D.Stanford University
Project Title: Molecular Mechanism and Novel Therapeutic Strategy in Alzheimer's Disease
Grant ID: DP2-AG-052940
Liang Feng is an assistant professor in the department of Molecular and Cellular Physiology at Stanford University School of Medicine. He graduated from Tsinghua University with a B.S. and obtained a master’s degree (M.Phil.) from the Hong Kong University of Science and Technology. He conducted his Ph.D. thesis work with Dr. Yigong Shi at Princeton University and completed his postdoctoral training with Dr. Roderick MacKinnon at the Rockefeller University. The Feng lab is interested in the structure, function, dynamic properties and therapeutic applications of membrane proteins. Liang Feng is also a Sloan Research Fellow and Klingenstein-Simons Fellow.
Karunesh Ganguly, M.D., Ph.D.University of California, San Francisco (UCSF) & San Francisco VA Medical Center (SFVAMC)
Project Title: Neuroprosthetic Control of an Anthropomorphic Exoskeleton in Tetraplegics
Grant ID: DP2-HD-087955
Karunesh Ganguly is an Assistant Professor at UCSF and a Staff Physician in the Neurology & Rehabilitation Service at the SFVAMC. He graduated from Stanford University and then received a Ph.D. in Neuroscience and a M.D. degree from the University of California, San Diego. After his neurology residency at UCSF, he completed a four-year postdoctoral fellowship in neural engineering in the Carmena Laboratory in the Department of EECS at UC Berkeley. His past awards include a Burroughs Wellcome Fund Career Award in Medicine, a Career Development Award (CDA) from the Veterans Health Affairs, and the Presidential Career Award for Scientists and Engineers (PECASE). The Ganguly laboratory conducts both basic and clinical research with the aim of translating neuroprosthetics to those with motor paralysis.
Marc Gershow, Ph.D.New York University
Project Title: Dissecting Olfactory Decision Making Using Optical Neurophysiology
Grant ID: DP2-EB-022359
Marc Gershow received a Ph.D. in Physics from Harvard University working with Jene Golovchenko on single molecule sequencing, did his postdoctoral work with Aravi Samuel in Harvard’s Center for Brain Science, and is currently an assistant professor in the Department of Physics at NYU. Marc studies how brains process information and make decisions, choosing the fruit fly larva as a model. Using state of the art optical tools to measure and perturb neural activity and techniques from physics, engineering, and computer vision, his lab aims to decipher the neural circuits underlying odor guided decision making.
Kamil Godula, Ph.D.University of California San Diego
Project Title: In Vivo Glycan Engineering at the Cell-Matrix Interface to Control Stem Cell Fate
Grant ID: DP2-HD-087954
Kamil Godula is an Assistant Professor in the Department of Chemistry and Biochemistry at UC San Diego. He earned his M.Sc. in organic chemistry with William A. Donaldson at Marquette University and his Ph.D. with Dalibor Sames at Columbia University, working in the area of C–H bond activation. He trained as a postdoctoral fellow with Carolyn Bertozzi at UC Berkeley, moving from chemical synthesis toward bio-nanomaterials and chemical glycobiology. Since 2013, he has led his own research laboratory at UCSD focusing on developing chemical approaches and nanotechnologies to study how spatial arrangements of glycans on cell-surface proteins encode biological information and how this information can be harnessed to control the outcomes of cellular differentiation. He is the recipient of the Alfred Bader Fellowship and the NIH Pathway to Independence Award.
Jesse H. Goldberg, M.D., Ph.D.Cornell University
Project Title: Identifying Pathways for Motor Variability in the Mammalian Brain
Grant ID: DP2-HD-087952
Jesse Goldberg is an Assistant Professor in the Department of Neurobiology and Behavior at Cornell University. He received a B.S. in biology from Haverford College and an M.D./Ph.D. degree from Columbia University. During his graduate work with Rafael Yuste, he used two photon imaging to study microcircuits of the cerebral cortex. After his Ph.D., he returned to the clinic and became interested in movement disorders. He received a Damon Runyon Fellowship to study the basal ganglia with Michale Fee at MIT. Dr. Goldberg’s current research focuses on the neural circuits underlying motor control and learning. His research is supported by the Klingenstein Foundation, the Pew Charitable Trust, and a BRAIN initiative award from the National Science Foundation.
Juliana Idoyaga, Ph.D.Stanford University
Project Title: Harnessing Human Dendritic Cell Subsets for the Design of Novel Immunotherapies
Grant ID: DP2-AR-069953
Juliana Idoyaga has a longstanding interest in dendritic cells. She trained in immunology and dendritic cell biology during her B.S. at the University of Buenos Aires in Argentina and during her Ph.D. at the National Autonomous University of Mexico. For her postdoctoral training, she joined the laboratory of Dr. Ralph Steinman at the Rockefeller University and focused on dendritic cell-based vaccines. She then spent two years working with Dr. Miriam Merad at the Icahn School of Medicine at Mount Sinai dissecting the contribution of radioresistant skin dendritic cells in tumor progression. She was appointed Assistant Professor of Microbiology and Immunology at Stanford University in July 2014. Her research program focuses on understanding dendritic cell subsets, revealing their endowed capacity to induce distinct types of immune responses, and designing novel strategies to exploit them for vaccines and therapies.
Daniel Jarosz, Ph.D.Stanford University
Project Title: Protein-Based Molecular Memories in Gene Regulation, Disease, and Development
Grant ID: DP2-GM-119140
Funded by the National Institute of General Medical Sciences
Dan Jarosz is an Assistant Professor in the Departments of Chemical & Systems Biology and Developmental Biology at Stanford University. He received his B.S. in Chemistry and Biochemistry from the University of Washington in 2001, and then moved to Massachusetts Institute of Technology for his Ph.D., where he investigated mechanisms of replication and mutagenesis in the laboratory of Dr. Graham Walker. Following his graduation in 2007, Dr. Jarosz received a fellowship from the Damon Runyon Cancer Research Foundation to pursue postdoctoral training with Dr. Susan Lindquist, a pioneer in the field of protein folding. In 2013, Dr. Jarosz established his independent group at Stanford University, where his research is focused on molecular mechanisms that influence robustness and evolvability. The Jarosz lab employs multidisciplinary systems approaches ranging from chemical biology to quantitative genetics to understand how these mechanisms contribute to evolution, disease, and development. In addition to receiving the NIH Director’s New Innovator Award, Dr. Jarosz has been named a Searle Scholar and a Kimmel Scholar and has received a Pathway to Independence Award from the NIH and a CAREER Award from the NSF.
Jakob D. Jensen, Ph.D.University of Utah
Project Title: Communal Feedback as an Innovative Alternative to Skin Self-Exam
Grant ID: DP2-EB-022360
Jakob D. Jensen graduated with honors from Concordia College where he was also an AFA National Champion in public speaking. His interest in public speaking led Dr. Jensen to pursue graduate education in the Department of Communication at the University of Illinois, where he received an M.A. (2003) and Ph.D. (2007) focused on health communication. Dr. Jensen is currently an Associate Professor in the Department of Communication at the University of Utah, and a member of the Cancer Control & Population Sciences Core in the Huntsman Cancer Institute. He directs the Health Communication and Technology (HCAT) lab which designs and evaluates innovative communication solutions to public health problems. Dr. Jensen’s primary research program seeks to improve skin cancer control by redesigning telehealth systems, and enhancing lay ability to identify atypical lesions.
Martin C. Jonikas, Ph.D.Carnegie Institution for Science
Project Title: Transforming Our Understanding of Eukaryotic Gene Functions through Chemical Genetics in the Green Alga Chlamydomonas reinhardtii
Grant ID: DP2-GM-119137
Martin Jonikas is a Staff Associate at the Carnegie Institution for Science and an Assistant Professor by courtesy at Stanford University. His laboratory aims to transform our understanding of photosynthetic eukaryotes by developing and applying cutting-edge tools. He studied aerospace engineering as an undergraduate at the Massachusetts Institute of Technology. He then received his Ph.D. from the University of California, San Francisco working with Jonathan Weissman, Maya Schuldiner and Peter Walter on high-throughput genetics and protein folding in the endoplasmic reticulum. He is the recipient of several awards, including a 2015 NIH New Innovator Award, a 2010 Air Force Young Investigator Award, and a 2005 National Science Foundation Graduate Research Fellowship.
Martin Kampmann, Ph.D.University of California, San Francisco
Project Title: Rewiring of the Human Protein Homeostasis Network in Normal and Disease Contexts
Grant ID: DP2-GM-119139
Funded by the National Institute of General Medical Sciences
Dr. Martin Kampmann is an Assistant Professor in the UCSF Department of Biochemistry and Biophysics and the Institute for Neurodegenerative Diseases. He received his B.A. and M.A. in Natural Sciences (Biochemistry) from Cambridge University and his Ph.D. from The Rockefeller University, where he used biophysical approaches to characterize the architecture and dynamics of the nuclear pore complex with Dr. Günter Blobel. As a postdoctoral fellow in Dr. Jonathan Weissman's group at UCSF, Dr. Kampmann spearheaded the development of a functional genomics platform that enables systematic genetic interaction maps in mammalian cells to uncover pathways underlying biological processes of interest. In his independent lab, he continues to pioneer functional genomics approaches and combines them with mechanistic biochemistry and biophysics to elucidate the role and rewiring of the protein homeostasis network in disease states of human cells, especially cancer and neurodegenerative diseases. Dr. Kampmann was awarded the NIH Pathway to Independence Award in 2014, and was named an Allen Distinguished Investigator by the Paul G. Allen Family Foundation in 2015.
Zachary A. Knight, Ph.D.University of California, San Francisco
Project Title: Sequencing Neural Circuits Controlling Thermoregulation
Grant ID: DP2-DK-109533
Zachary Knight is an Assistant Professor in the Department of Physiology at University of California, San Francisco. He received his B.A. in Chemistry from Princeton University and his Ph.D. in Chemical Biology from UCSF. As a graduate student he synthesized some of the first selective inhibitors of PI3-kinase and mTOR and used those tools to study signaling pathways involved in metabolism and cancer. He then performed postdoctoral research at the Rockefeller University, where developed methods for using RNA sequencing to identify functional populations of neurons in the mouse brain. His lab at UCSF studies neural circuits in the mouse that control feeding and other innate behaviors, using a combination of optical, genetic, and physiologic approaches.
Darren J. Lipomi, Ph.D.University of California, San Diego
Project Title: Stretchable, Biodegradable, and Self-Healing Semiconductors for Wearable and Implantable Sensors
Grant ID: DP2-EB-022358
Darren J. Lipomi earned his undergraduate degree in chemistry from Boston University in 2005. Under Prof. James S. Panek, his research focused on total synthesis and heterogeneous catalysis for applications in medicinal chemistry. He earned his Ph.D. in chemistry from Harvard University in 2010, with Prof. George M. Whitesides, where he developed several unconventional approaches to micro- and nanopatterning for chemical sensing. From 2010-2012, he was an Intelligence Community Postdoctoral Fellow in the laboratory of Prof. Zhenan Bao at Stanford University, and worked in the area of electronic skin. He is now an assistant professor in the Department of NanoEngineering at the University of California, San Diego, where his work focuses on biomimetic organic semiconductors in applications in energy and healthcare.
Chang C. Liu, Ph.D.University of California, Irvine
Project Title: A High-Throughput Continuous Evolution System for In Vivo Biosensor Engineering
Grant ID: DP2-GM-119163
Chang C. Liu received his A.B. in Chemistry from Harvard in 2005 and his Ph.D. in Chemical Biology from The Scripps Research Institute, where he trained with Peter Schultz. After carrying out his postdoctoral work with Adam Arkin as a Miller Fellow at UC Berkeley, Chang joined UC Irvine as an Assistant Professor in 2013. Chang’s group is interested in building genetic systems that give cells radically new capabilities. These include continuous evolution of target genes, recording non-genetic information, and synthesizing unnatural polymers. In addition to the New Innovator Award, Chang’s research been recognized by a Beckman Young Investigator Award, a Dupont Young Professor Award, and grants from DARPA and NSF.
Deepika Mohan, M.D., M.P.H.University of Pittsburgh School of Medicine
Project Title: A Novel Intervention to Make Heuristics a Source of Power for Physicians
Grant ID: DP2-LM-012339
Deepika Mohan is an Assistant Professor of Critical Care Medicine and Surgery at the University of Pittsburgh. Dr. Mohan received a B.A. in religion and political theory from Princeton University in 1997, an M.D. from Emory University in 2001, and an M.P.H. from Columbia University in 2003. She completed her general surgery residency at Emory University in 2007, and her critical care fellowship at the University of Pittsburgh in 2008. Her research focuses on the role of heuristics in physician decision making, particularly time-sensitive decisions like the triage of trauma patients or the treatment of septic patients.
James B. Munro, Ph.D.Tufts University School of Medicine
Project Title: Structural Dynamics of Single Ebolavirus GP Molecules
Grant ID: DP2-AI-124384
Funded by the National Institute of Allergy and Infectious Diseases
James Munro joined the Department of Molecular Biology and Microbiology at Tufts University School of Medicine in October of 2014, as an assistant professor. He came to Tufts from Yale University, where he was an Irvington Postdoctoral Fellow of the Cancer Research Institute in the laboratory of Walther Mothes. While in the Mothes lab, Dr. Munro developed a single-molecule fluorescence-based approach to probe the conformational dynamics of the HIV envelope glycoprotein on the surface of native virions. Prior to that, Dr. Munro completed a Ph.D. in biophysics from Cornell University, working in the laboratory of Scott Blanchard at Weill Cornell Medical College, and an M.S. in physics from the University of Chicago. Dr. Munro completed his undergraduate studies in physics at Middlebury College.
Matthew J. Paszek, Ph.D.Cornell University
Project Title: Mechanobiology of the Cellular Glycocalyx
Grant ID: DP2-GM-119133
Matthew Paszek received his B.S. in chemical engineering from Cornell University, and his Ph.D. in bioengineering from the University of Pennsylvania. His thesis work with Daniel Hammer and Valerie Weaver investigated physical mechanisms underlying cancer progression. He conducted his postdoctoral research with Valerie Weaver at UCSF, where he began his work in glycoscience, and later with Claudia Fischbach-Teschl and Abraham Stroock as a Kavli Fellow at Cornell University, where he continued to develop imaging tools for glycoscience. In 2014, he joined the faculty in the Department of Chemical and Biomolecular Engineering at Cornell University, where his group studies biophysical mechanisms of glycan function.
Jennifer E. Phillips-Cremins, Ph.D.University of Pennsylvania
Project Title: Engineering 3-D Epigenome Topology with Light
Grant ID: DP2-MH-110247
Jennifer E. Phillips-Cremins, Ph.D., joined the faculty at the University of Pennsylvania in 2014 as an Assistant Professor in the Department of Bioengineering and a core member of the Epigenetics Program in the Perelman School of Medicine. Dr. Cremins obtained her Ph.D. in Biomedical Engineering from the Georgia Institute of Technology in the laboratory of Andres Garcia. She then conducted a unique multi-disciplinary postdoc in the laboratories of Victor Corces and Job Dekker with the goal of generating the first high-resolution 3-D genome architecture maps during the differentiation of mouse embryonic stem cells along the neuroectoderm lineage. Dr. Cremins now runs the 3-D Epigenomics and Systems Neurobiology laboratory at UPenn. Her primary research interests lie in understanding the epigenetic mechanisms that govern phenotype commitment in healthy neurons and how these epigenetic mechanisms go awry during the onset of neurodevelopmental and neurodegenerative diseases. She has been selected as a 2014 New York Stem Cell Foundation – Robertson Investigator and a 2015 Albert P. Sloan Foundation Fellow in addition to the 2015 NIH Director's New Innovator Award.
Manu Prakash, Ph.D.Stanford University
Project Title: Mosquitoes Meet Microfluidics: Novel Tools for Ecological Surveillance of Insect-Borne Disease
Grant ID: DP2-AI-124336
Manu Prakash was born in Meerut, India and did his B.Tech at Indian Institute of Technology, Kanpur in Computer Science. For his Ph.D., Manu worked in an Applied Physics lab of Neil Gershenfeld at Massachusetts Institute of Technology developing new microfluidics technology platforms. In 2008, Manu was appointed a Junior Fellow at the Harvard Society of Fellows for a period of three years, and developed novel imaging tools applied to insect metamorphosis. In 2011, Manu started a curiosity driven lab at the Department of Bioengineering at Stanford University. The lab develops scientific tools for the masses, including ultra-low cost tools for biosciences and global health (e.g. Foldscope). Recent work in the lab focuses on developing novel and scalable-tools for global surveillance of mosquitoes and arthropod borne diseases.
Abhishek Prasad, Ph.D.University of Miami
Abhishek Prasad is an Assistant Professor in the Department of Biomedical Engineering at the University of Miami, FL. He received his M.S. in Biomedical Engineering from Louisiana Tech University and Ph.D. in Biomedical Engineering from New Jersey Institute of Technology and University of Medicine and Dentistry in New Jersey. The goal of his laboratory is to develop brain and spinal cord machine interfaces to restore communication and control in paralyzed individuals. Toward enabling these neuroprosthetic technologies to interface the nervous system with devices, his laboratory uses electrophysiology, computational tools, and functional electrical stimulation in both healthy and injury models. His laboratory is also involved in neural probe development by understanding and mitigating various abiotic and biotic mechanisms in neural electrode failure.
Gregory W. Schwartz, Ph.D.Feinberg School of Medicine, Northwestern University
Project Title: Novel Circuit Mapping Strategies to Reverse Engineer the Retina
Grant ID: DP2-EY-026770
Greg Schwartz received a B.S./M.S. in Neuroscience and a B.A. in Computer Science from Brandeis University in 2003, where his thesis work investigated the influence of context in human recognition memory. He began studying visual processing in the retina during his graduate work in the laboratory of Michael J. Berry at Princeton University where he received his Ph.D. in 2008. Dr. Schwartz continued studying the retina as a post-doc in the laboratory of Fred Rieke at the University of Washington where he also collaborated closely with Rachel Wong to link anatomical and functional measurements into bottom-up retinal circuit models. As an Assistant Professor of Ophthalmology and Physiology at Northwestern University since 2013, Dr. Schwartz and his lab are developing new strategies to map retinal circuits by combining electrophysiology, imaging, genetics, and computational modeling.
Evan A. Scott, Ph.D.Northwestern University
Evan Scott is an Assistant Professor of Biomedical Engineering within Northwestern University’s McCormick School of Engineering and Applied Science. He respectively received a B.S. and Ph.D. in Biomedical Engineering from Brown University in 2002, and Washington University in St. Louis in 2009, where his dissertation work was completed under the guidance of Prof. Donald Elbert. As a Whitaker International Scholar, he performed postdoctoral research in Switzerland in the laboratories of Prof. Jeffrey Hubbell and Prof. Melody Swartz at the École Polytechnique Fédérale de Lausanne (EPFL). Dr. Scott is a recipient of the American Heart Association Scientist Development Grant, the National Science Foundation CAREER Award, and the NIH Director’s New Innovator Award. His laboratory applies principles from bionanotechnology and tissue engineering towards the development of translational immunotherapies for heart disease and the rational design of vaccines.
Mohammad R. Seyedsayamdost, Ph.D.Princeton University
Project Title: Implementing Innovative Approaches to Access the Hidden Metabolomes of Bacteria
Grant ID: DP2-AI-124786
Mohammad R. Seyedsayamdost is an Assistant Professor in the Departments of Chemistry and Molecular Biology at Princeton University. His research group is interested in the discovery, structure, function, and biosynthesis of microbial metabolites with therapeutic properties. Dr. Seyedsayamdost received a combined B.S./M.S. degree with highest honors in Biochemistry from Brandeis University, working under the guidance of Prof. Lizbeth Hedstrom, and subsequently carried out his graduate studies in the laboratory of Prof. JoAnne Stubbe in the Department of Chemistry at MIT. Supported by a Life Sciences Research Foundation postdoctoral fellowship and an NIH Pathway to Independence Award, he conducted postdoctoral studies in the research groups of Prof. Jon Clardy and Prof. Roberto Kolter at Harvard Medical School. Dr. Seyedsayamdost has been the recipient of the Searle Scholars Award, the Pew Biomedical Scholars Award, the Princeton Environmental Institute’s Innovative Research Award, and recently, the NIH Director's New Innovator Award.
Alex K. Shalek, Ph.D.Massachusetts Institute of Technology/Ragon Institute of MGH, MIT and Harvard/Broad Institute of MIT and Harvard
Project Title: "Bottom - Up" Profiling of Interacting Cellular Systems
Grant ID: DP2-GM-119419
Alex K. Shalek is currently the HLF von Helmholtz Career Development Assistant Professor of Health Sciences and Technology at MIT, as well as a Core Member of the Institute for Medical Engineering and Science (IMES) and an Assistant Professor of Chemistry. He is also an Associate Member of the Ragon and Broad Institutes, and an Assistant in Immunology at MGH. His research is directed towards the development and application of new technologies that facilitate understanding of how cells collectively perform systems-level functions in healthy and diseased states. Alex received his bachelor’s degree summa cum laude from Columbia University, his Ph.D. from Harvard University in chemical physics under the guidance of Hongkun Park, and performed his postdoctoral training under Hongkun Park and Aviv Regev (Broad/MIT). To date, his interdisciplinary research has focused on realizing and utilizing nanoscale manipulation and measurement technologies to examine how small components (molecules, cells) drive systems of vast complexity (cellular responses, population behaviors).
Matthew D. Shoulders, Ph.D.Massachusetts Institute of Technology
Project Title: Continuous Directed Evolution of Biomolecules in Human Cells for Medical Research
Grant ID: DP2-GM-119162
Matthew Shoulders is an Assistant Professor in the Department of Chemistry at the Massachusetts Institute of Technology. His research focuses on designing chemical biology methods to modulate and monitor protein folding in metazoan cells, as well as applying those methods in protein misfolding-related disease model systems to reveal new fundamental aspects of cellular proteostasis and to potentially identify new therapeutic strategies. Prior to beginning his independent position at MIT, Prof. Shoulders was an American Cancer Society Postdoctoral Fellow in Prof. Jeffery Kelly’s research group at the Scripps Research Institute in La Jolla, CA. He conducted his Ph.D. research in organic chemistry with Prof. Ronald Raines at the University of Wisconsin–Madison, where he was a USA Department of Homeland Security Graduate Fellow. Prof. Shoulders earned his B.S. in chemistry Summa cum Laude from Virginia Tech in 2004.
Robert C. Spitale, Ph.D.University of California, Irvine
Project Title: Cracking the RNA Localization Code
Grant ID: DP2-GM-119164
Robert Spitale received his Ph.D. with Professor Joseph Wedekind at the University of Rochester, where he studied the structural basis of gene regulation in non-coding RNA enzymes and metabolite-responsive RNAs. After graduating he relocated to California where he studied under the guidance of Professor Howard Chang at Stanford University. There, he focused on developing a novel method of probing RNA structure transcriptome-wide within living cells. These studies were done in collaboration with Professor Eric Kool's lab. Robert started as an Assistant Professor in the Department of Pharmaceutical Sciences at the University of California, Irvine in July 2014. His lab aims to combine the precision of chemistry and the wide-field view of transcriptomics to address currently unanswerable questions regarding the structure and function of RNA molecules.
Cole Trapnell, Ph.D.University of Washington
Project Title: Charting the Regulatory Topography of the Cell Differentiation Landscape with Single-Cell RNA-Seq
Grant ID: DP2-HD-088158
Cole Trapnell received bachelor's degrees in Computer Science and Mathematics in 2005 from the University of Maryland and returned there to earn a Ph.D. in 2010 under the guidance of Steven Salzberg and Lior Pachter. He wrote TopHat and Cufflinks, which together constitute one of the most widely used workflows for analyzing transcriptome sequencing data. He trained as postdoc in John Rinn's lab at Harvard University, where he studied long noncoding RNAs in embryonic stem cell differentiation and somatic cell reprogramming. He also developed Monocle, a tool for analyzing single-cell genomics experiments, which now powers his lab at the University of Washington's Department of Genome Sciences.
Marmar Vaseghi, M.D., M.S.University of California, Los Angeles
Project Title: Cardiac Afferent Neurotransmission and Modulation of Ventricular Parasympathetic Control
Grant ID: DP2-HL-132356
Dr. Marmar Vaseghi is an Assistant Professor at University of California, Los Angeles. She received her B.S. in Biomedical Engineering from Northwestern University and her M.D. from Stanford University. Her cardiology and electrophysiology training were completed at UCLA where she simultaneously obtained her Masters in Clinical Research from the Department of Biomathematics and Specialty Training and Advance Research Program. Dr. Vaseghi’s laboratory focuses on understanding neural remodeling in the setting of cardiomyopathy and neural modulation of arrhythmias. Utilizing electrophysiological and neural recording techniques in a porcine infarct model, her laboratory studies alterations in cardiac neurotransmission in health and disease and its impact on arrhythmogenesis. Furthermore, her interest lies in studying mechanisms of arrhythmias and effects of neuromodulatory therapies in patients with heart failure. In addition to the New Innovator Award, Dr. Vaseghi is also the recipient of the National American Heart Association Fellow to Faculty Transition Award.
Melissa R. Warden, Ph.D.Cornell University
Project Title: Imaging the Evolving Neural Circuit Dynamics of Depression
Grant ID: DP2-MH-109982
Melissa Warden is an Assistant Professor and Miriam M. Salpeter Fellow in the Department of Neurobiology and Behavior at Cornell University. She received an A.B. in Molecular Biology from Princeton University and a Ph.D. in Systems Neuroscience from the Massachusetts Institute of Technology, where she investigated prefrontal neuronal encoding of multi-item short-term memory with Earl K. Miller. As a postdoctoral fellow with Karl Deisseroth at Stanford University she studied cortical control of neuromodulatory systems in motivated behavior. Her research at Cornell integrates imaging, neurophysiological, and cellular and molecular approaches to study the neural circuits mediating reward and motivated behavior and their dysfunction. She has received a number of awards including the NIH Director’s New Innovator Award, a Robertson Neuroscience Investigator Award from the New York Stem Cell Foundation, a NARSAD Young Investigator Award from the Brain and Behavior Research Foundation, a Sloan Research Fellowship from the Alfred P. Sloan Research Foundation, and a Research Grant from the Whitehall Foundation.
Jessica L. Whited, Ph.D.Harvard Medical School and Brigham & Women's Hospital
Project Title: Leveraging Single-Cell Analysis to Elucidate Mechanisms of Vertebrate Limb Regeneration
Grant ID: DP2-HD-087953
Jessica Whited graduated from the University of Missouri with a B.S. in Biological Sciences and a B.A. in Philosophy. She earned a Ph.D. in Biology from MIT, where she studied development and maintenance of neuronal architecture in Drosophila under the mentorship of Dr. Paul Garrity. As a postdoctoral fellow in the laboratory of Dr. Clifford Tabin at Harvard Medical School, Jessica pursued the question of limb regeneration, where she built a colony of axolotl salamanders and developed tools for interrogating their biology. She is currently an Assistant Professor in the Department of Orthopedic Surgery at BWH, a member of the Brigham Regenerative Medicine Center, and a Smith Family Foundation and March of Dimes Basil O’Connor awardee. The Whited lab aims to understand, at a molecular level, the amazing ability of axolotls to completely regenerate legs so that these insights can later be applied to the human condition.
Min Yu, M.D., Ph.D.University of Southern California
Project Title: Developing Individualized Medicine Targeting Metastatic Breast Cancer Stem Cells
Grant ID: DP2-CA-206653
Dr. Min Yu received her medical degree from Shandong Medical University, master in neurology from Peking University Health Science Center, and Ph.D. in genetics from SUNY Stony Brook and Cold Spring Harbor Laboratory (CSHL). Her thesis work with Dr. Senthil Muthuswamy at CSHL investigated mammary epithelial cell morphogenesis on a three-dimensional culture system. With a desire to apply basic research to clinical questions, she pursued postdoctoral training with Dr. Daniel Haber at Massachusetts General Hospital, Harvard Medical School, where she characterized circulating tumor cells isolated from the peripheral blood of cancer patients. Dr. Yu joined the Department of Stem Cell Biology and Regenerative Medicine and the USC Norris Comprehensive Cancer Center as an assistant professor in 2014, and her lab focuses on the mechanisms of cancer metastasis. In addition to the NIH Director’s New Innovator Award, she received the NCI career transition (K22) award, the STOP CANCER Research Career Development Award, the Pew-Stewart Scholar for Cancer Research award, and the Donald E. & Delia B. Baxter faculty fellowship.
Wenjun Zhang, Ph.D.University of California Berkeley
Project Title: In Situ Natural Product Labeling and Applications
Grant ID: DP2-AT-009148
Dr. Wenjun Zhang is an Assistant Professor in the Department of Chemical and Biomolecular Engineering at University of California, Berkeley, and the Charles R. Wilke Endowed Chair in Chemical Engineering. Her research focuses on understanding and engineering the biosynthesis of natural products for applications related to both human health and bioenergy and is supported by the Energy Biosciences Institute, the PEW Scholars Program, the Hellman Fellows Fund, and NIH. Dr. Zhang received her B.S. and M.S. in Biochemistry from Nanjing University, China, and her Ph.D. in Chemical Engineering in the laboratory of Dr. Yi Tang at University of California, Los Angeles with an honor. She did her postdoctoral training under the mentorship of Dr. Christopher T. Walsh at Harvard Medical School.
Adam R. Abate, Ph.D.University of California, San Francisco
Project Title: Microfluidic Immunoprofiling for Biomarker Discovery in Rheumatoid Arthritis
Grant ID: DP2-AR-068129
Adam R. Abate graduated from Harvard College in 2002, with an A. B. in Physics. He received his Ph.D. in Physics at the University of Pennsylvania in 2006, studying soft materials and driven non-equilibrium granular systems with Douglas Durian. He returned to Harvard for a postdoc in Physics in the lab of David Weitz, working on a variety of projects in soft matter physics, chemical and microparticle synthesis, and biological applications of microfluidics. While a postdoc, he developed a droplet-based microfluidic sequencer that became the foundation for the sequencing company GnuBIO. He also has a company, Mission Bio, commercializing PCR-Activated Cell Sorting (PACS), a technology developed in his lab. He is an Assistant Professor at the University of California, San Francisco in the Department of Bioengineering and Therapeutic Sciences in the Schools of Medicine and Pharmacy and the California Institute for Quantitative Biosciences (QB3) and is part of the joint Berkeley-UCSF bioengineering graduate program, PSPG, and iPQB. He was Awarded the NSF CAREER Award in 2013, and the NIH New Innovator Award in 2014. His research interests are to apply droplet-based microfluidics and NGS for ultrahigh-throughput single cell biology.
Murat Acar, Ph.D.Yale University
Project Title: Quantitative Real-Time Characterization of Single-Cell Aging: From Phenotypes to Lifespan
Grant ID: DP2-AG-050461
Murat Acar received his B.S. degree in Physics from Bogazici University in 2000, and his Ph.D. degree in Physics from MIT in 2007. As a graduate student working with Alexander van Oudenaarden at MIT, he studied feedback regulation and genetic noise in gene networks. After his doctoral studies, Murat moved to CalTech as a CBCD Fellow and completed his postdoctoral studies in Frances Arnold's laboratory. Using baker’s yeast as an model organism, he studied dosage compensation in genetic circuits. Murat joined Yale's Department of Molecular, Cellular & Developmental Biology as an Assistant Professor in 2012; he is also a faculty member at the Yale Physics Department and a core member of the Yale Systems Biology Institute. Among the awards and honors Murat has received are a 2014 New Innovator Award by the NIH and a 2013 New Scholar in Aging Award by the Ellison Medical Foundation.
Satyanarayana Ande, Ph.D.Georgia Regents University Cancer Center
Project Title: A Multifaceted Approach to Target Obesity
Grant ID: DP2-DK-105565
Satyanarayana Ande obtained his Master’s degree (MSc) from Nagarjuna University, India. He earned his Ph.D. from the Department of Gastroenterology and Hepatology at the Hannover Medical School, Germany where he investigated the role of telomerase and telomere dysfunction in liver regeneration and liver tumorigenesis. Later, he performed his postdoctoral studies in the fields of liver cancer and obesity at the National Cancer Institute-Frederick (NCI/NIH). In 2013, he received NCI career transition (K22) award and obtained independent research position at the Georgia Regents University. Dr. Ande is an Assistant Professor in the Georgia Regents University Cancer Center and his laboratory research mainly focuses on obesity, liver cancer and cancer metabolism studies.
Mark L. Andermann, Ph.D.Beth Israel Deaconess Medical Center
Project Title: Multiphoton Imaging of Thoughts of Food During Natural and Induced Hunger States
Grant ID: DP2-DK-105570
Mark Andermann, Ph.D., is a researcher in the Division of Endocrinology, Diabetes, and Metabolism at Beth Israel Deaconess Medical Center. He is also a faculty member of the Harvard Program in Neuroscience and an assistant professor of medicine at Harvard Medical School (HMS). Dr. Andermann graduated from McGill University in 1999 with a joint honors degree in mathematics and physics, and received his Ph.D. in biophysics and neuroscience in 2005 from Harvard University, where he began to investigate the brain mechanisms underlying tactile sensory perception in rats. He completed a one-year postdoctoral fellowship at the Helsinki University of Technology, where he designed a novel sensory brain-computer interface for use in humans. Dr. Andermann then went on to complete his postdoctoral training at HMS in the laboratory of Clay Reid, Ph.D., where he developed a mouse model for studying visual perception in which neural activity in the same brain cells can be recorded for many months in behaving mice. Dr. Andermann’s lab uses leading-edge brain imaging techniques to study the brain networks guiding hunger-dependent attention to food cues—a key first step toward developing cognitive therapies for obesity, binge eating, and other eating disorders.
Robert Anthony, Ph.D.Harvard Medical School
Project Title: Glycoengineering In Vivo
Grant ID: DP2-AR-068272
Robert Anthony is an Assistant Professor at Harvard Medical School, Assistant Immunologist at Massachusetts General Hospital, and Principle Investigator at the Center for Immunology and Inflammatory Diseases. Robert’s laboratory examines the role and regulation of immunoglobulin glycosylation in autoimmune and allergic diseases, and was established in 2012. Robert received a B.A. in biology from Franklin and Marshall College, Ph.D. in molecular and cell biology at USUHS under the supervision of Bill Gause and Joe Urban, and conducted his postdoctoral research with Jeffrey Ravetch at the Rockefeller University (New York, NY).
Reza Ardehali, Ph.D.University of California Los Angeles
Project Title: Exploring Heterogeneity of Cardiac Fibroblasts to Reverse Fibrosis
Grant ID: DP2-HL-127728
Reza Ardehali received his Ph.D. in Bioengineering. After finishing medical school, he completed his Internal Medicine residency at Johns Hopkins, followed by cardiology training at Stanford. He joined UCLA as an assistant professor in 2012. His research focuses on mechanisms of cardiovascular development with an emphasis on the generation of novel regenerative approaches to treat heart disease. His group has identified several fibroblast populations in the heart derived from discrete developmental origin. Using modified RNAs, cardiac fibroblasts can be reprogrammed to cardiomyocyte-like cells following a dose-titratable, temporally-controlled, and stage-specific sequential delivery of key transcription factors involved in cardiomyoycte specification. The ultimate goal of his research is to develop strategies to regenerate the damaged myocardium following an injury.
Manish Arora, B.D.S., M.P.H., Ph.D.Icahn School of Medicine at Mount Sinai
Project Title: Reconstructing Fetal Toxicant Exposure and Homeostatic Disruptions
Grant ID: DP2-ES-025453
Manish Arora is an exposure biologist with training in dentistry, nuclear beam methods and analytical chemistry. In 2013, he joined the Icahn School of Medicine at Mount Sinai where he directs the Exposure Biology Lab. He has proposed a ‘biologic hard drive’ approach centered on the analysis of human deciduous and permanent teeth to reconstruct the life history of environmental exposures. This approach is being applied to understand the environmental determinants of a number of priority disorders including, autism spectrum disorders, schizophrenia, and amyotrophic lateral sclerosis.
Yimon Aye, Ph.D.Cornell University
Project Title: Deconvoluting Redox Biology with Targeted Chemistry
Grant ID: DP2-GM-114850
Aye received her undergraduate degree in chemistry with 1st-class honors from the University of Oxford, UK (2000-2004). She conducted her final-year thesis research with Professor Stephen G. Davies at Oxford University (2003-2004), and her undergraduate summer research with Professor Stephen L. Buchwald at MIT (2003 summer). Aye subsequently received her graduate training in organic chemistry with Professor David A. Evans at Harvard University (2004-2009). With a firm desire to help solve complex biomedical problems with chemistry and chemical intuition, Aye decided to switch her research focus in chemical sciences and received her postdoctoral training in life sciences as a Damon Runyon Cancer Research Fellow with Professor JoAnne Stubbe at MIT (2009-2012). As of July 2012, Aye is a Milstein assistant professor of Chemical Biology at Cornell University with a secondary appointment at Weill Cornell Medical College as an assistant professor of Biochemistry.
Michael C. Bassik, Ph.D.Stanford University
Project Title: Accelerating Drug Development and Repurposing Using Systematic Genetic Interactions
Grant ID: DP2-HD-084069
Michael Bassik received his undergraduate degree from the University of Wisconsin-Madison. His Ph.D. work at Harvard Medical School focused on the role of BCL-2 family proteins in regulating cell death in the laboratory of Stanley Korsmeyer. He then did his postdoctoral work in the laboratory of Jonathan Weissman at UCSF, where he helped develop a novel platform for creating high-throughput pairwise genetic interaction maps in mammalian cells. His new laboratory in the Department of Genetics at Stanford continues to develop technologies to conduct high throughput screens using both shRNA and CRISPR/Cas9 systems, and applies these tools to (1) identify novel drug targets and synergistic combinations, and (2) understand the cellular response to stresses and endocytic pathogens such as bacteria and protein toxins.
Roberto Bonasio, Ph.D.University of Pennsylvania
Project Title: Studying Epigenetic Pathways in Brain Function and Social Behavior Using Ants
Grant ID: DP2-MH-107055
Roberto Bonasio did his undergraduate studies at the University of Milan and received his Ph.D. in immunology from Harvard in 2006. He obtained further postodctoral training at NYU in the laboratory of Danny Reinberg, studying chromatin biochemistry and functional genomics. During his postdoc Roberto led an international team that sequenced and analyzed the first ant genomes. In 2014, he joined the Epigenetics Program at the University of Pennsylvania School of Medicine, where his laboratory studies the molecular mechanisms of epigenetics in conventional systems and emerging model organisms, such as ants. The NIH Director’s New Innovator award will allow the Bonasio laboratory to fully establish the ant Harpegnathos saltator as a model system by developing genetic tools, molecular markers, and epigenomic profiles.
Mitesh Borad, M.D.Mayo Clinic Arizona
Project Title: Oncolytic Virotherapy in Hepatocellular Cancer
Grant ID: DP2-CA-195764
Mitesh J. Borad received his B.S. in Biomedical Engineering from Boston University in 1996, and M.D. from Rutgers New Jersey Medical School in 2000. After completing his internal medicine training at Cedars-Sinai Medical Center in Los Angeles and medical oncology training at Tulane University School of Medicine in New Orleans, he was a Genomics Medicine and Drug Development Scholar at the Translational Genomics Research Institute in Phoenix under the tutelage of Dr. Daniel Von Hoff. His research efforts are focused on development of novel therapeutics in liver, biliary and pancreatic cancers by leveraging Next-gen whole genome sequencing approaches, as well as application of emerging areas, such as the use of recombinant viruses with oncolytic/immunotherapeutic properties. His group was the first to introduce an oncolytic Rhabdovirus into human clinical studies, and further development of this exciting area will be a focus of his efforts.
Timothy J. Buschman, Ph.D.Princeton University
Project Title: Developing an Adaptive Cognitive Prosthetic to Replace Damaged Brain Regions
Grant ID: DP2-EY-025446
Hu Cang, Ph.D.Salk Institute for Biological Studies
Project Title: Ultra Sensitive Single Molecule Spectroscopy with Plasmonic Antennas
Grant ID: DP2-EB-020400
Hu Cang is an Assistant Professor in the Waitt Advanced Biophotonics Center at the Salk Institute for Biological Studies. He received a M.S. in Electrical Engineering and a Ph.D. in Chemistry from the Stanford University. Prior to that, he received his B.S. degree in Chemical Physics from the University of Science and Technology of China. His research focuses on developing ultra-sensitive spectroscopy tools to probe the structural and dynamics of single molecules.
Ibrahim Cisse, Ph.D.Massachusetts Institute of Technology
Project Title: Imaging Transcription with Single Molecule Resolution in Live Mammalian Cells
Grant ID: DP2-CA-195769
Ibrahim Cissé joined the Department of Physics at MIT in January 2014, from HHMI’s Janelia Research Campus where he had been in the Transcription Imaging Consortium since January 2013. Prior to this, he was in Paris from January 2010 to December 2012, at Ecole Normale Supérieure de Paris, jointly in the departments of Physics and Biology, as a Pierre Gilles de Gennes fellow and a European Molecular Biology Organization long-term fellow. He received his Ph.D. from the Physics Department at the University of Illinois at Urbana-Champaign in December 2009. His graduate research in single-molecule biophysics was with Taekjip Ha, focusing on weak and transient interactions in vitro. He received his B.S. in Physics in 2004, from North Carolina Central University, and during that time he was investigating packing of ellipsoids using M&M candies with Paul M. Chaikin. Ibrahim is native of Niger, where he lived before moving to the US for college.
Sarah Cobey, Ph.D.University of Chicago
Project Title: Modeling the Evolutionary Dynamics of Immunity to Influenza for Vaccine Development
Grant ID: DP2-AI-117921
Ethan C. Garner, Ph.D.Harvard University
Project Title: Dissecting Bacterial Cell Wall Synthesis Using In Vivo Single Molecule Tracking
Grant ID: DP2-AI-117923
Ethan Garner was born in Richland, Washington. He received his B.S. in biochemistry from Washington State University, where he worked with Keith Dunker developing tools to predict disordered regions within proteins. He conducted his Ph.D. with Dyche Mullins at UCSF, where he kinetically dissected and reconstituted plasmid DNA segregation by prokaryotic polymers. Ethan conducted his postdoc in Boston, working for Tim Mitchison, Xiaowei Zhuang, and David Rudner. His lab started at the Harvard Center for Systems Biology in 2012, where his group studies the motions of bacterial enzymes and how they build cell shape.
Lindsey L. Glickfeld, Ph.D.Duke University
Project Title: Context-Dependent Changes in Local and Long-Range Cortical Circuits
Grant ID: DP2-EY-025439
Lindsey Glickfeld received a B.S. in Biological Sciences with distinction from Stanford University in 2002, and a Ph.D. in Neurosciences from the University of California at San Diego in 2007. Her thesis work with Dr. Massimo Scanziani investigated the function of diverse classes of inhibitory interneurons in cortical circuits. With a desire to understand the function of these circuits in vivo, Dr. Glickfeld pursued a postdoctoral fellowship with Dr. Clay Reid where she learned advanced microscopy approaches and visual neuroscience. Before starting an independent position, Dr. Glickfeld spent a year training with Dr. John Maunsell to develop behavioral paradigms that can be used to study vision in rodent models. Dr. Glickfeld is currently an Assistant Professor in the Department of Neurobiology at Duke University where her lab focuses on the cellular and circuit mechanisms that support the processing of sensory input in the visual cortex.
Andrew P. Goodwin, Ph.D.University of Colorado
Project Title: Rapid, Multiscale Sensing Using Acoustic Detection Mechanisms
Grant ID: DP2-EB-020401
Andrew Goodwin joined the Department of Chemical and Biological Engineering at the University of Colorado at Boulder as an Assistant Professor in 2012. His research focuses on designing “smart” colloids and materials – such as polymeric architectures, organic/inorganic hybrids, and multiphase composites – that can sense their surroundings and change their chemical and physical properties accordingly. He is also interested in how interfaces organize themselves when sensing chemical stimuli and also how they respond to external forces. Prior to CU, Prof. Goodwin was an NIH Postdoctoral Fellow in the Department of Nanoengineering at the University of California, San Diego, where he received a K99 Pathway to Independence Award in Cancer Nanotechnology, a DOD Breast Cancer Postdoctoral Fellowship, and an AACR Scholar-in-Training Award. He obtained his Ph.D. in Chemistry from the University of California, Berkeley and his B.A. in Chemistry from Columbia University in New York.
Elissa A. Hallem, Ph.D.University of California Los Angeles
Project Title: The Neural Basis of Odor-Driven Behavior in Skin-Penetrating Parasitic Nematodes
Grant ID: DP2-DC-014596
Elissa Hallem is an Assistant Professor in the Department of Microbiology, Immunology, and Molecular Genetics at UCLA. Her lab studies sensory neural circuits in free-living and parasitic nematodes, with an emphasis on how parasitic worms use sensory cues to locate hosts to infect. Dr. Hallem received a B.A. in biology and chemistry from Williams College, and a Ph.D. in neuroscience from Yale University. After completing a postdoctoral fellowship at Caltech, she joined the UCLA faculty in 2011. Dr. Hallem is the recipient of a 2015 Burroughs-Wellcome Fund Investigators in the Pathogenesis of Disease Award, a 2013 McKnight Scholar Award, a 2012 MacArthur Fellowship, a 2012 Searle Scholar Award, a 2011 Alfred P. Sloan Fellowship, and a 2011 Rita Allen Foundation Fellowship.
Christine P. Hendon, Ph.D.Columbia University, New York Morningside
Project Title: High Resolution Imaging of the Myocardium
Grant ID: DP2-HL-127776
Dongeun Huh, Ph.D.University of Pennsylvania
Project Title: Probing the Physics of Chronic Lung Disease Using Microphysiological Biomimicry
Grant ID: DP2-HL-127720
‘Dan’ Dongeun Huh is the Wilf Family Term Assistant Professor in Bioengineering at the University of Pennsylvania. He received his B.S. in Mechanical Engineering from Seoul National University, M.S. and Ph.D. in Biomedical Engineering from the University of Michigan. He then joined Harvard University as a postdoctoral researcher and completed his training as a Wyss Technology Development Fellow at Harvard’s Wyss Institute for Biologically Inspired Engineering where he pioneered the “Organ-on-a-Chip” technology. At Penn, Dan is leading an interdisciplinary research group that focuses on developing innovative biomimetic micro- and nanoengineering technologies for biomedical, pharmaceutical, and environmental applications. His primary research interest is in the development and application of microengineered physiological cell culture models that recapitulate structural and functional complexity of living human organs during health and disease.
Nicholas T. Ingolia, Ph.D.University of California Berkeley
Project Title: Molecular Basis and Cellular Roles of Translational Regulation
Grant ID: DP2-CA-195768
Nicholas Ingolia is an Assistant Professor of Molecular and Cell Biology at the University of California, Berkeley. His laboratory applies genome-scale and unbiased approaches to study the molecular basis underlying the translational control of gene expression and the roles of this regulation in cellular and organismal physiology. He studied math and biology as an undergraduate at the Massachusetts Institute of Technology and then received his Ph.D. from Harvard University under the supervision of Andrew Murray. As a post-doctoral fellow with Jonathan Weissman at the University of California, San Francisco, he developed the ribosome profiling approach for global and comprehensive measurements of translation. He continued to develop and apply ribosome profiling in his own lab at the Carnegie Institution Department of Embryology prior to joining the faculty at UC Berkeley in January of 2014.
Michelle C. Janelsins, Ph.D., M.P.H.University of Rochester
Project Title: Clinical and Translational Approaches to Cognitive Impairments in Cancer
Grant ID: DP2-CA-195765
Dr. Michelle Janelsins is tenure-track Assistant Professor of Surgery and Oncology at University of Rochester, Director of the Cancer Control and Psychoneuroimmunology Laboratory, and Chair of Translational Science for the UR NCORP Research Base. She received her Ph.D. in 2008, in the areas of microbiology, immunology, and neuroscience and fellowship in 2011, in the areas of clinical cancer control, neuropsychology, and cognitive science. Following her fellowship, she completed an M.P.H. in clinical investigation and public health. All graduate training was completed at University of Rochester and Wilmot Cancer Institute. Dr. Janelsins’ laboratory focuses on understanding clinical, psychological, and biological contributors of cancer-related cognitive impairment and on interventions to alleviate cancer-related cognitive impairment including clinical trials, longitudinal studies and animal modeling.
Cigall Kadoch, Ph.D.Dana-Farber Cancer Institute
Project Title: Reversing Oncogenic BAF Complex Structure & Function: New Therapeutic Approaches
Grant ID: DP2-CA-195762
Sriram Kosuri, Sc.D.University of California Los Angeles
Project Title: Reverse Genomics of Regulatory Elements Governing Splicing
Grant ID: DP2-GM-114829
Sri Kosuri received his B.S. in Bioengineering at UC Berkeley working with Prof. Adam Arkin on bacterial systems biology in 2001. He received his Sc.D. in Biological Engineering at MIT with Prof. Drew Endy working on systems and synthetic biology of bacteriophage T7 development in 2007. He was the first employee of Joule Unlimited from 2007-2009, and returned to academics as a member of the Advanced Technology team at the Wyss Institute working with Prof. George Church. There he developed large-scale gene synthesis technologies combined with multiplexed measurements based on next-generation sequencing to better understand sequence determinants of gene expression. In 2014, he became an Assistant Professor of Chemistry and Biochemistry at UCLA. His laboratory develops new technologies in DNA synthesis, sequencing, and genome engineering and applies them to both study and engineer biology. At UCLA, he is a member of the UCLA-DOE Institute for Genomics and Proteomics, the Institute for Quantitative and Computational Biology, the Broad Center of Regenerative Medicine and Stem Cell Research, the Johnson Comprehensive Cancer Center, and the Molecular Biology Institute. Dr. Kosuri was awarded the NIH Director's New Innovator Award in 2014, and was named a Searle Scholar in 2015.
Pamela K. Kreeger, Ph.D.University of Wisconsin-Madison
Project Title: Analysis of How Quantitative Cellular Network Variation Impacts Tumor Progression
Grant ID: DP2-CA-195766
Pamela Kreeger is an Assistant Professor in the Department of Biomedical Engineering at the University of Wisconsin-Madison. She earned a B.S. in Chemistry from Valparaiso University, a Ph.D. in Chemical Engineering at Northwestern University working with Lonnie Shea and Teresa Woodruff, and was a post-doctoral fellow in Biological Engineering at MIT in Doug Lauffenburger’s lab. Her lab utilizes tools from systems biology and tissue engineering to determine how variations in protein expression interact with changes in the disease microenvironment to influence cellular phenotypic decisions. She is the recipient of a NSF CAREER award and is an American Cancer Society Research Scholar.
Gabriel C. Lander, Ph.D.Scripps Research Institute
Project Title: Molecular Basis of Axonal Transport Described by High-Resolution 3D Imaging
Grant ID: DP2-EB-020402
Gabriel Lander is faculty member of the Department of Integrative Structural and Computational Biology at The Scripps Research Institute, where he uses electron microscopy to study cellular events. Gabriel received a B.S. from the State University of New York at Binghamton, where he performed structural analyses of colchicine, an anti-inflammatory drug, and its interactions with tubulin, which inspired him to pursue a career in structural biology. Gabriel was first introduced to electron microscopy during his graduate work at The Scripps Research Institute, exploring the mechanics of virus assembly and infection under the joint guidance of Jack Johnson, Bridget Carragher, and Clint Potter. Gabriel then moved to UC Berkeley and received a Damon Runyon fellowship to perform his postdoctoral work in lab of Eva Nogales, examining the structural mechanisms that govern microtubule dynamics. At Berkeley Gabriel also collaborated with Andreas Martin to decipher the mechanisms of protein degradation by the 26S proteasome. As an assistant professor at The Scripps Research Institute, Gabriel is the recipient of the Searle and Pew awards in addition to the Innovator Award.
Chenxiang Lin, Ph.D.Yale University
Project Title: Cell-Free Membrane Remodeling Guided by DNA Nano-Templates
Grant ID: DP2-GM-114830
Chenxiang Lin is an Assistant Professor of Cell Biology at Yale University. He studied Chemistry at Peking University from 2000 to 2004, and did his Ph.D. thesis on structural DNA nanotechnology with Prof. Hao Yan at Arizona State University from 2005 to 2009. He continued his research in biomolecular nanotechnology as a research fellow with Prof. William Shih at Dana-Farber Cancer Institute, Wyss Institute at Harvard and Harvard Medical School from 2009 to 2012. In September 2012, he moved to Yale University, where he leads a research team that focuses on developing DNA-nanostructure-based molecular tools for biological studies.
Leonard Lipovich, Ph.D.Wayne State University
Project Title: Life, Death, and Function: The Primate-Specific Long Non-Coding RNA Transcriptome
Grant ID: DP2-CA-196375
Leonard Lipovich, a proud graduate of Stuyvesant High School, New York City, earned his B.A. (cum laude) in Genetics and Development from Cornell University (Ithaca, N.Y.) in 1998, and his Ph.D. in Genome Sciences from the University of Washington, Seattle, where Mary-Claire King was his dissertation advisor, in 2003. After postdoctoral training at the Genome Institute of Singapore, where he discovered the first ever mammalian long non-coding RNA directly functional in stem cell pluripotency, and pioneered the concept of sense-antisense gene pair evolutionary non-conservation, Dr. Lipovich joined Wayne State University in Detroit, Michigan in 2007 as an assistant professor, and was promoted to associate professor with tenure in 2013. In 2014, Dr. Lipovich received the NIH Director's New Innovator Award for his work on how primate-specific long non-coding RNAs cause cell growth and cell death in human cancer. Current research in the Lipovich laboratory interrogates the contribution of long non-coding RNA genes to human cancer and metabolic disorders, using integrated computational and experimental approaches: high-throughput reverse genetics, non-coding RNA proteogenomics, and Genome-Wide Association Studies. Dr. Lipovich, a funded co-investigator of the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium, pursues a long-term goal of improving human health through personalized, lncRNA-targeted rational therapeutics.
Brent R. Martin, Ph.D.University of Michigan
Project Title: Multiscale Chemical Approaches to Map Oxidative Stress
Grant ID: DP2-GM-114848
Brent Martin is an Assistant Professor of Chemistry at the University of Michigan, Ann Arbor. He received both his B.S. in Molecular Biology and Ph.D. in Biomedical Sciences at UC San Diego. His thesis research with Roger Tsien involved the development and optimization of genetically encoded fluorescent probes for light and electron microscopy. He then carried out postdoctoral studies at the Scripps Research Institute with Benjamin Cravatt developing chemical probes and chemoproteomic strategies for profiling post-translational modifications. The Martin lab is currently developing multidisciplinary methods to explore the function and physiological role of novel enzymes and post-translational modifications involved in the development of neurological diseases and cancer.
Michael McAlpine, Ph.D.University of Minnesota
Project Title: 3D Printed Nano-Bionic Organs
Grant ID: DP2-EB-020537
Michael C. McAlpine is the Benjamin Mayhugh Associate Professor of Mechanical Engineering at the University of Minnesota. He received a B.S. in Chemistry with honors from Brown University (2000) and a Ph.D. in Chemistry from Harvard University (2006). His research is focused on 3D printing functional materials & devices, including the three-dimensional interweaving of biological and electronic materials using 3D printing. He has received a number of awards, including the Presidential Early Career Award for Scientists and Engineers (PECASE), NIH Director’s New Innovator Award, a TR35 Young Innovator Award, an Air Force Young Investigator Award, the Intelligence Community Young Investigator Award, a DuPont Young Investigator Award, a National Academy of Sciences Frontiers Fellow, a DARPA Young Faculty Award, an American Asthma Foundation Early Excellence Award, a Graduate Student Mentoring Award, the Extreme Mechanics Letters Young Lecturer, and an invitation to the National Academy of Engineering Frontiers in Engineering.
Mala Murthy, Ph.D.Princeton University
Project Title: How Does the Brain Solve the Pattern Recognition Problem?
Grant ID: DP2-NS-092378
Mala Murthy is an Assistant Professor in the Princeton Neuroscience Institute and Department of Molecular Biology at Princeton University. She received a B.S. in Biology from MIT, a Ph.D. in Neuroscience from Stanford University, and did postdoctoral research at Caltech. Her research is focused on how the brain extracts salient information from the sensory world and uses this information to modulate behavior. She uses the genetically tractable model system Drosophila and studies its acoustic behaviors using a combination of quantitative behavioral assays, in vivo neural recordings, and computational modeling. During courtship, male flies produce dynamic songs while females arbitrate mating decisions based on song information; research in the Murthy lab is solving the cellular-level neural mechanisms that link sensory processing to behavior, in the context of communication. Her research has won numerous other awards including from the McKnight Foundation, the Klingenstein-Simons Foundation, the Sloan Foundation, the Human Frontiers Science Program, and the National Science Foundation (both a CAREER award and a BRAIN Initiative grant).
Gregor Neuert, Ph.D.Vanderbilt University
Project Title: Decoding the Noncoding Genome: lncRNA Dynamics and Function in Single Cells
Grant ID: DP2-GM-114849
Gregor Neuert is an Assistant Professor in the Department of Molecular Physiology and Biophysics at Vanderbilt University School of Medicine. During his Ph.D. in Physics he worked in the area of single-molecule biophysics with Hermann Gaub at Ludwig Maximilians University Munich. With a DFG-Fellowship, he did his postdoctoral studies in the area of single cell systems biology with Alexander van Oudenaarden at Massachusetts Institute of Technology. The Neuert lab works on the leading edge in the quantitative understanding of molecular mechanism contributing to the function and malfunction of signal transduction and gene regulatory processes of coding and non-coding RNA in single yeast and mammalian cells. To address this question, our research combines single molecule and single cell methodologies with genetics and computational and molecular biology.
Michael Rosenblum, M.D., Ph.D.University of California San Francisco
Project Title: Functional Manipulation of Memory Regulatory T cells in Skin
Grant ID: DP2-AR-068130
Michael Rosenblum is a formally trained basic immunologist and a practicing dermatologist. He received his M.D. and Ph.D. degrees form the Medical College of Wisconsin and did his residency in Dermatology at UCSF. After completion of his residency, Dr. Rosenblum did a post-doctoral fellowship in the laboratory of Abul Abbas at UCSF. Currently, he dedicates 85% of his time to basic research and the remaining time taking care of patients with specific inflammatory and autoimmune skin diseases. The central focus of his laboratory is to understand the fundamental mechanisms of how immune responses are regulated in peripheral tissues, and how this knowledge can be exploited for therapeutic benefit.
June Round, Ph.D.University of Utah
Project Title: Developing Therapies to Target the Microbiota
Grant ID: DP2-AT-008746
June Round received her Ph.D from University of California, Los Angeles in 2007, where she studied how early T cell signals lead to distinct cellular functions in the laboratory of M. Carrie Miceli. She moved to Caltech for her postdoctoral studies in the laboratory of Sarkis Mazmanian studying how commensal bacteria coordinated host immune responses to enforce its colonization within the intestine and utilizing commensal products to induce tolerogenic responses. She is currently an Assistant professor in the Department of Pathology at the University of Utah. Her lab is interested in understanding how various members of the microbiota and host immune system interact to influence diseases such as inflammatory bowel disease and multiple sclerosis. She was awarded the Edward Mallinckrodt Jr Foundational grant in 2012, NSF CAREER award in 2012, Pew Foundational grant in 2013, and Packard Fellowship in Science and Engineering in 2013.
John W. Schoggins, Ph.D.UT Southwestern Medical Center
Project Title: Discovery of Antiviral Mechanisms in Bats
Grant ID: DP2-AI-117922
John Schoggins is an Assistant Professor in the Department of Microbiology at UT Southwestern Medical School in Dallas, TX. He was recruited to UT Southwestern under the Endowed Scholars Program and is named the Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in Honor of Dr. Bill S. Vowell. John trained as a postdoctoral fellow with Charlie Rice at Rockefeller University and received his Ph.D. in the laboratory of Erik Falck-Pedersen at Weill Cornell Medical School in New York City. His primary research interests are innate immune responses to viral infection and virus-host interactions. In addition to the New Innovator Award, John is also the 2015 Rita Allen Foundation Milton E. Cassel Scholar.
Agnel Sfeir, Ph.D.New York University School of Medicine
Project Title: Telomere-Independent Strategies to Protect Chromosome Ends
Grant ID: DP2-CA-195767
Dr. Agnel Sfeir received her B.S and M.Sc. in Biology from the American University of Beirut. She then moved to the U.S. to pursue her Ph.D. in Cell Biology in the laboratory of Jerry Shay and Woodring Wright at the University of Texas Southwestern Medical Center. After completing her post-doctoral training with Titia de Lange at the Rockefeller University, she joined the Skirball Institute at NYU School of Medicine as an assistant professor in January of 2012. Her research focuses on how mammalian cells ensure the stability of their genomes. In addition to the NIH Director’s New Innovator Award, she received the Pew-Stewart Scholarship for Cancer research, Damon Runyon-Rachleff Innovator Award, V-Foundation Scholar Award, Human FrontierScience Program Young Investigator Award, and an award from The David and Lucile Packard Foundation.
Matthew Simon, Ph.D.Yale University
Project Title: Integrating RNAs into Signaling Pathways by Engineering Covalent RNA Modification
Grant ID: DP2-HD-083992
Sarah E. Stabenfeldt, Ph.D.Arizona State University-Tempe Campus
Project Title: Detecting and Treating Traumatic Brain Injury Pathology Progression from the Inside
Grant ID: DP2-HD-084067
Dr. Sarah Stabenfeldt received her B.S. in Biomedical Engineering from Saint Louis University and her Ph.D. in Bioengineering from Georgia Institute of Technology. She continued her training as a NIH post-doctoral fellow at Emory University School of Medicine and Georgia Tech focusing on protein-protein interactions. She joined Arizona State University’s School of Biological and Health Systems Engineering as an Assistant Professor in 2011, and leads her research team in developing regenerative medicine strategies for traumatic brain injury. Since joining ASU, Dr. Stabenfeldt has been awarded the Arizona Biomedical Research Consortium Early Stage Investigator Award, the NIH Director’s New Innovator Award, and NSF CAREER Award. The New Innovator award enables Dr. Stabenfeldt to pursue unique diagnostic and therapeutic approaches for traumatic brain injury.
Michiko Taga, Ph.D.University of California Berkeley
Project Title: Targeted Killing of Bacteria in Communities
Grant ID: DP2-AI-117984
Dr. Michi Taga is an Assistant Professor in the Department of Plant & Microbial Biology at the University of California, Berkeley. Her research uses genetics, biochemistry, analytical chemistry, and bioinformatics to investigate how bacteria share nutrients within complex microbial communities. Dr. Taga developed the corrinoid (vitamin B12) model to study metabolic interactions among bacteria. The New Innovator award enables her to broaden her study of microbial interactions by examining the ecological roles of specific bacteria within their communities. Dr. Taga received a B.A. in Biology from Carleton College and a Ph.D. in Molecular Biology from Princeton University. She began her study of vitamin B12 as a postdoctoral scholar at M.I.T.
Lin Tian, Ph.D.University of California at Davis
Project Title: Fluorescent Biosensors for Imaging Neurotransmitters: Observing Synapses in Action
Grant ID: DP2-MH-107056
Dr. Lin Tian is an Assistant Professor in the department of Biochemistry and Molecular Medicine at the University of California, Davis. Her lab is dedicated to research that combines the development of optical sensors and applications in order to acquire fundamental insight about how the nervous system functions in health and disease. Her research will contribute to a steady advancement of the ability of the “age of light” to reveal functional connectivity in the neural circuitry. Dr. Tian has been awarded the Rita Allen Young Scholar, Hartwell Individual Biochemical Researcher, Human Frontier Program Young Investigator and NIH Brain Initiative. The new Innovator award enables Dr. Tian to engineer much needed imaging tools to enable neuroscientists to obtain a comprehensive view of both excitatory and inhibitory synapses in action at the cellular, tissue, and whole-animal level.
Leo Q. Wan, Ph.D.Rensselaer Polytechnic Institute
Project Title: Cell Chirality Based In Vitro Models for Embryonic Development and Abnormalities
Grant ID: DP2-HD-083961
Dr. Leo Q. Wan is an assistant professor in the Department of Biomedical Engineering at the Rensselaer Polytechnic Institute in Troy, NY. He received his Bachelor and Master degrees in Mechanical Engineering from the University of Science and Technology of China. After completing his Ph.D. in Biomedical Engineering at Columbia University in 2007 (with Professor Van C. Mow), he became a postdoctoral scientist in the Laboratory for Stem Cells and Tissue Engineering (with Professor Gordana Vunjak-Novakovic). His current research interests focus on understanding physical biology in tissue development and regeneration, and include Tissue Morphogenesis, Stem Cell Mechanobiology, and Functional Tissue Engineering. In addition to the NIH Director’s New Innovator Award, Leo is also a Pew scholar (Class 2013), and recipient of National Science Foundation Early Career Award, American Heart Association Scientist Development Grant, and the March of Dimes Basil O’Connor Starter Scholar Research Award.
Daniel J. Westreich, Ph.D.University of North Carolina Chapel Hill
Project Title: From Patients to Policy: Innovative Epidemiology for Implementation Science
Grant ID: DP2-HD-084070
Dr. Daniel Westreich received his B.S. in computer science from Yale University (1998), and his M.S.P.H. and Ph.D. in Epidemiology from UNC-Chapel Hill (2005; 2008). After postdoctoral training at UNC-Chapel Hill, he served as an assistant professor of Obstetrics & Gynecology and Global Health at Duke University; he then became an assistant professor of Epidemiology at UNC-Chapel Hill. At UNC, Dr. Westreich’s current work focuses methodologically on epidemiologic methods for causal inference and implementation science, and substantively at the intersection of HIV and reproductive health, as well as HIV and chronic diseases. Dr. Westreich serves as an associate editor of the American Journal of Epidemiology, and was the inaugural recipient of the Brian MacMahon Early Career Epidemiologist award from the Society for Epidemiologic Research.
Rong Xu, Ph.D.Case Western Reserve University
Project Title: Rapid Reverse Translational Drug Repositioning
Grant ID: DP2-HD-084068
Lei Yang, Ph.D.University of Pittsburgh at Pittsburgh
Project Title: Toward Regeneration of Whole Bioartificial Human Heart
Grant ID: DP2-HL-127727
Lei Yang received a B.S in Biology from Wuhan University in China in 1997, and earned his Ph.D. degree from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, in 2003. After finishing his PhD, he did a postdoctoral fellowship in Developmental Biology at UCSD with Dr. Sylvia Evans and then joined the laboratory of Dr. Gordon Keller as a postdoctoral fellow in Stem Cell Biology at the Mount Sinai School of Medicine in NYC. He started his tenure track Assistant Professor position in the department of Developmental Biology at University of Pittsburg and established the Stem Cell Core Facility in 2010. He is also currently an adjunct Assistant Professor in the department of Bioengineering at University of Pittsburgh School of Engineering. His lab utilizes a combination of human embryonic stem (ES) cells, human induced pluripotent stem (iPS) cells, tissue engineering and mouse genetic models to understand early stage human heart development, study molecular mechanisms of human inherited heart diseases, and regenerate whole personalized bio-artificial heart for heart disease therapy.
Lili Yang, Ph.D.University of California Los Angeles
Project Title: Stem Cell-Engineered Invariant Natural Killer T Cells for Cancer Therapy
Grant ID: DP2-CA-196335
Lili received her B.S. degree in Biology from the University of Science & Technology of China (USTC) in 1997, her M.S. degree in Biomedical Sciences from the University of California, Riverside (UCR) in 1999, and her Ph.D. degree in Biology from the California Institute of Technology (Caltech) in 2004. She obtained her Ph.D. training at the Laboratory of David Baltimore. Post graduation, she stayed at Caltech and led a multi-institutional Engineering Immunity Program from 2004 to 2012, developing gene- and cell-based immunotherapies for cancer and HIV/AIDS. Her work resulted in 23 publications, 8 patents and 2 clinical trials. She joined the University of California, Los Angeles (UCLA) as an Assistant Professor in January of 2013. Her laboratory at UCLA studies tumor immunology and cancer immunotherapy, with a special focus on stem cell-engineered immunotherapy for cancer. Besides the NIH Director’s New Innovator Award, she also received multiple other awards including the TR35 Award, the Forbeck Scholar Award, the CHARVI/HVTN Early Career Investigator Award, the CIRM Basic Biology V Exploratory Concepts Award, the STOP CANCER Research Career Development Award, and the Prostate Cancer Foundation GTSN Challenge Award.
Lijie Grace Zhang, Ph.D.George Washington University
Project Title: A Novel 3D Bioprinted Smart Vascularized Nano Tissue
Grant ID: DP2-EB-020549
Dr. Lijie Grace Zhang is an associate professor in the Department of Mechanical and Aerospace Engineering, Department of Biomedical Engineering and Department of Medicine at the George Washington University. Her main research is to integrate 3D bioprinting and nanotechnology for complex tissue and organ regeneration. She obtained her Ph.D. in Biomedical Engineering at Brown University with distinction in 2009. After finishing her postdoctoral trainings at Rice University and Harvard Medical School, she joined GW. She has received the Young Innovator in Cellular and Molecular Bioengineering, GW SEAS Outstanding Young Researcher Award, John Haddad Young Investigator Award by American Society for Bone and Mineral Research, Early Career Award from the International Journal of Nanomedicine, and Ralph E. Powe Junior Faculty Enhancement Award by the Oak Ridge Associated Universities Organization, etc.
Weian Zhao, Ph.D.University of California Irvine
Project Title: Mechano-Sensing Stem Cells to Study, Detect and Treat Cancer Metastases
Grant ID: DP2-CA-195763
Weian Zhao is an Assistant Professor at the Department of Pharmaceutical Sciences, University of California, Irvine. Dr. Zhao completed his B.Sc. and M.Sc. degrees in Chemistry at Shandong University where he studied polymer, surface and colloidal chemistry. In 2008, he received his Ph.D. degree in Chemistry at McMaster University, where he focused on the use of functional nucleic acid to structure gold nanoparticles to construct well-defined nanostructures and biosensors. Dr. Zhao then completed a Human Frontier Science Program (HFSP) Postdoctoral Fellow at Harvard Medical School, Brigham and Women’s Hospital and MIT. Dr. Zhao received the MIT’s Technology Review TR35 Award: the world’s top 35 innovators under the age of 35 in 2012. Dr. Zhao’s current research focuses on the development of novel molecular, nano- and micro-engineered tools for stem cell therapy and regenerative medicine, diagnosis and in vivo imaging, and elucidating stem cell and cancer biology.
Roberto Zoncu, Ph.D.University of California Berkeley
Project Title: Engineering Organelle Function to Rewire Cancer Cell Metabolism
Grant ID: DP2-CA-195761
Roberto Zoncu is an Assistant Professor in the Molecular and Cell Biology Department at the University of California, Berkeley. His research focuses on how organelles known as lysosomes participate in nutrient sensing and metabolic signal transduction, and how disruption of organelle homeostasis contributes to cancer growth. Roberto received his B.S. from the University of Pisa, Italy. He then moved to the U.S. to pursue Ph.D. studies in the laboratory of Pietro De Camilli at Yale University, and completed postdoctoral training under the supervision of David Sabatini at the Whitehead Institute for Biomedical Research. In addition to the Innovator Award, Roberto is the recipient of a Pew-Stewart Scholarship for Cancer Research and an Edward J Mallinckrodt Research Grant.
Chenghang Zong, Ph.D.Baylor College of Medicine
Project Title: Detecting the Onset of Genome Heterogeneity in Tumor at Single Cell Resolution
Grant ID: DP2-EB-020399
Hillel Adesnik, Ph.D.University of California, Berkeley
Project Title: New Optical Strategies to Unlock the Neural Basis of Perception
Grant ID: DP2-NS-087725
Hillel Adesnik received his Ph.D. at UCSF under Roger Nicoll, where worked on the molecular mechanisms of learning and memory. He did his postdoctoral work with Massimo Scanizani at UCSD where he studied cortical microcircuitry underlying spatial computations in the brain. He is currently an Assistant Professor of Neurobiology at UC Berkeley. His lab's goal is to develop and leverage new optical tools to address the neural basis of perception and neural computation in the cerebral cortex.
Jennifer Ahern, Ph.D.University of California, Berkeley
Project Title: A Rigorous System to Determine the Health Impacts of Policies and Programs
Grant ID: DP2-HD-080350
Dr. Jennifer Ahern, Ph.D., M.P.H., is an Associate Professor of Epidemiology at the University of California, Berkeley, and a Chancellor’s Professor. She examines the effects of the social and physical environment, and programs and policies that alter the social and physical environment, on many aspects of health (e.g., substance use, mental health, violence, and gestational health). Dr. Ahern has a methodological focus to her work, including application of causal inference methods and semi-parametric estimation approaches, aimed at improving the rigor of observational research, and optimizing public health intervention planning.
Bree B. Aldridge, Ph.D.Tufts University
Project Title: Quantitative Design of Multi-Drug Regimens for Tuberculosis
Grant ID: DP2-LM-011952
Bree Aldridge is an assistant professor in the Department of Molecular Biology and Microbiology and an adjunct assistant professor in the Department of Biomedical Engineering at Tufts University. Dr. Aldridge began combining biology and engineering during her undergraduate work at the University of Arizona, where she completed B.S. degrees in Molecular and Cellular Biology and Computer Engineering and worked with Drs. Samuel Ward and François Cellier. She went on to train with Drs. Douglas Lauffenburger and Peter Sorger during her graduate studies in Biological Engineering at MIT. During her Ph.D., Dr. Aldridge developed computational and experimental techniques to understand the complexity of cell fate decisions in cancer cells. She then trained with Dr. Sarah Fortune at the Harvard School of Public Health where she established tools to study cell-to-cell heterogeneity in mycobacteria. Her lab uses quantitative, single cell approaches to understand drug tolerance and virulence in Mycobacterium tuberculosis.
Sara Aton, Ph.D.University of Michigan
Project Title: Linking Network Activity and Intracellular Plasticity Mechanisms During Sleep-Dependent Memory Consolidation
Grant ID: DP2-MH-104119
Sara Aton is an Assistant Professor in the Department of Molecular, Cellular, and Developmental Biology at the University of Michigan. Her Ph.D. thesis research, which identified intercellular and intracellular signaling pathways required for neural network dynamics within the mammalian circadian clock, was carried out in the laboratory of Dr. Erik Herzog at Washington University in St. Louis. She then carried out postdoctoral research aimed at identifying cellular and network mechanisms for sleep dependent plasticity in the developing visual system, in the laboratory of Dr. Marcos Frank at the University of Pennsylvania. The Aton lab now investigates two sleep-dependent processes in the adult mammalian brain - response plasticity in thalamocortical circuits following novel sensory experience, and consolidation of hippocampally-mediated long-term memory following single-trial learning. These studies employ a combination of cutting-edge electrophysiological, opto- and pharmacogenetic, behavioral, biochemical, and computational techniques to elucidate the role of sleep in promoting brain plasticity.
Catherine A. Blish, M.D., Ph.D.Stanford University School of Medicine
Project Title: Harnessing Natural Killer Cell Memory to Fight Viruses
Grant ID: DP2-AI-112193
Catherine Blish, M.D., Ph.D. is an Assistant Professor of Medicine and Immunology at the Stanford University School of Medicine and an Assistant Director of the Stanford Medical Scientist Training Program (MSTP). Her research aims to understand the successes and failures of the immune system in order to better harness it to prevent infections. After receiving a B.S. in Biochemistry with Highest Honors from the University of California, Davis, she matriculated in the MSTP at the University of Washington School of Medicine, receiving her M.D. and a Ph.D. in Immunology. After residency in Internal Medicine she pursued a fellowship in Infectious Disease and the University of Washington, with a research focus on immune correlates of HIV-1 infection. She has received numerous awards for research and mentoring, including the Stanford Immunology Outstanding Faculty Mentor Award, the ICAAC Young Investigator Award from the American Society for Microbiology, the Beckman Young Investigator Award, the McCormick Faculty Award, the Baxter Faculty Scholar, and the Doris Duke Charitable Foundation Clinical Scientist Development Award.
Jason M. Crawford, Ph.D.Yale University
Project Title: Cryptic Gut Bacterial Metabolites that Regulate Colorectal Cancer Formation
Grant ID: DP2-CA-186575
Jason M. Crawford has been an Assistant Professor of Chemistry and of Microbial Pathogenesis and a Member of the Chemical Biology Institute at Yale University since 2012. He carried out his doctoral research with Craig Townsend at the Johns Hopkins University, studying the biosynthesis of complex aromatic polyketide metabolites. He then carried out his postdoctoral research with Jon Clardy at Harvard Medical School, elucidating the structures of metabolites from novel secondary metabolic pathways that regulate host-bacteria interactions. He concluded his postdoctoral training as a National Institutes of Health Pathway to Independence Fellow with Jon Clardy, Christopher Walsh, and Roberto Kolter. The Crawford lab combines the disciplines of microbial biosynthesis, genetics, metabolomics, and small molecule structural elucidation to discover and characterize new bacterial metabolic pathways that regulate human host biology, such as the bacterial contributions to colorectal cancer development.
Arvin Dar, Ph.D.Icahn School of Medicine at Mount Sinai
Project Title: Targeting Ras-Dependent Cancers with a Chemical Switch for an Inactive Kinase
Grant ID: DP2-CA-186570
Arvin Dar is an Assistant Professor of Oncological Sciences and Structural and Chemical Biology at the Icahn School of Medicine at Mount Sinai. He graduated with a B.Sc. in Chemistry from the University of Western Ontario and then completed his Ph.D. thesis at the University of Toronto in 2006. His thesis was done in the laboratory of Frank Sicheri where he studied the structure and regulation of protein complexes and viral inhibitors. Dr. Dar conducted postdoctoral studies with Kevan Shokat at the University of California, San Francisco, where he developed small molecule tools to control kinase structure and signaling in normal and cancer cells. Dr. Dar’s current research focuses on the use of target-based and systems pharmacology approaches to generate new classes of small molecule modulators for Ras-dependent cancers. Dr. Dar’s honors and awards include a Department of Defense Postdoctoral Fellowship, a UCSF Dean’s Prize, Innovator Awards from the NIH and the Damon-Runyon-Rachleff Foundation, a Pew-Stewart Scholarship in Cancer Research, and a Young Investigator Award from the Pershing Square Sohn Cancer Research Alliance.
Rahul C. Deo, M.D., Ph.D.University of California, San Francisco
Project Title: Resolving Incomplete Penetrance in the Cardiomyopathies and Channelopathies
Grant ID: DP2-HL-123228
Maximilian Diehn, M.D., Ph.D.Stanford University
Project Title: Developing a Genomic Approach for Cancer Screening
Grant ID: DP2-CA-186569
Jeffrey D. Dvorin, M.D., Ph.D.Boston Children's Hospital and Harvard Medical School
Project Title: Essential Gene Discovery in the Malaria Parasite Plasmodium falciparum
Grant ID: DP2-AI-112219
Jeffrey Dvorin is an Assistant Professor in Pediatrics at Harvard Medical School and an Associate Physician of Infectious Diseases at Boston Children’s Hospital. After he earned his M.D. and Ph.D. from the University of Pennsylvania, he completed a Pediatrics residency at Children’s Hospital of Philadelphia, and then a fellowship in Infectious Diseases at Boston Children’s Hospital. He completed his postdoctoral training at the Harvard School of Public Health in the laboratory of Manoj Duraisingh. In his laboratory, Dr. Dvorin’s research focuses on the molecular pathogenesis of infection by the human malaria parasite Plasmodium falciparum. His laboratory utilizes novel genetic techniques to understand the function of essential genes in the parasite.
Aaron P. Esser-Kahn, Ph.D.University of California, Irvine
Project Title: Directing the Immune System via Polymeric Combinations of Molecular Signals
Grant ID: DP2-AI-112194
Aaron Esser-Kahn is an Asst. Prof. of Chemistry at UC Irvine. His work looks at developing novel, chemical methods to activate and direct the immune system. His interests include spatial and temporal control of innate immune signaling and applications of adjuvant and vaccine development. He earned a Ph.D. at UC Berkeley as part of Chemical Biology Program. He was a post-doc a University of Illinois Urbana-Champaign working with the Autonomous Materials Systems group.
Scott E. Evans, M.D.The University of Texas M.D. Anderson Cancer Center
Project Title: Inducible Epithelial Antiviral Resistance to Prevent Asthma
Grant ID: DP2-HL-123229
Scott E. Evans is an Associate Professor in the Department of Pulmonary Medicine at the University of Texas MD Anderson Cancer Center. He received his doctoral degree at the University of Texas Medical School at San Antonio and completed his postdoctoral research training in the laboratory of Andrew H. Limper at the Mayo Clinic. Dr. Evans joined the faculty at MD Anderson in 2005 to study the prevention and management of pneumonia in the immunocompromised host. He directs a research program focused on manipulation of lung mucosal defenses to protect against pneumonia. Using a combination of mouse genetics and in vitro modeling, his laboratory has discovered a broadly protective therapeutic that is now in clinical trials.
Dorothea Fiedler, Ph.D.Princeton University
Project Title: Understanding Phosphate Metabolism in Cancer and Metastasis
Grant ID: DP2-CA-186753
Adam Frost, M.D., Ph.D.University of Utah School of Medicine
Project Title: Toward Atomic Resolution of Membranes and Membrane-Associated Machines
Grant ID: DP2-GM-110772
Sunil P. Gandhi, Ph.D.University of California Irvine
Project Title: Rewiring Cortex Using Inhibitory Neuron Transplantation
Grant ID: DP2-EY-024504
Sunil Gandhi is an Assistant Professor in the Department of Neurobiology and Behavior and a Fellow of the Center for the Neurobiology of Learning and Memory at the University of California, Irvine. He received a B.S. from Stanford University where he conducted research on visual attention in the laboratory of Dr. David Heeger. He earned his Ph.D. at University of California, San Diego working with Dr. Charles Stevens at the Salk Institute on synaptic vesicle recycling. He did his postdoctoral training at University of California, San Francisco with Dr. Michael Stryker studying the role of inhibition in cortical plasticity. He is a Searle Scholar, a Klingenstein-Simons Fellow and a recipient of the NIH Director’s New Innovator Award. His laboratory is focused on understanding the cellular mechanisms that create critical periods in brain development.
Zev J. Gartner, Ph.D.University of California, San Francisco School of Pharmacy
Project Title: Total Synthesis of the Human Mammary Gland
Grant ID: DP2-HD-080351
Zev Gartner is native to Santa Cruz, California. He received his B.S. in Chemistry from UC Berkeley in 1999, where he conducted undergraduate research in the laboratory of Y. K. Shin. He received his Ph.D. in Chemical Biology from Harvard University in 2004, where he worked with Professor David Liu to develop DNA-Templated Synthesis as a strategy for building and evolving drug-like small molecules. In 2005 he returned to UC Berkeley for postdoctoral training with Professor Carolyn Bertozzi. While in Professor Bertozzi’s lab, he explored DNA Programmed Assembly as a bottom-up method for building three-dimensional tissues. He is currently an Associate Professor in the Department of Pharmaceutical Chemistry at the University of California, San Francisco. Research in the Gartner Lab is focused on the role of tissue self-organization and other collective cell behaviors in human development and disease.
Viviana Gradinaru, Ph.D.California Institute of Technology
Project Title: Neuromodulation and Neurodegeneration: the Missing Link and Mechanisms of Action
Grant ID: DP2-NS-087949
Dr. Viviana Gradinaru is Assistant Professor of Biology and Biological Engineering at Caltech as well as the faculty director of the Beckman Institute Center for Optogenetics and CLARITY. She has recently been awarded the NIH Director’s New Innovator Award and been honored as a World Economic Forum Young Scientist and as one of Cell’s 40 under 40. Viviana is also a Sloan Fellow, Pew Scholar, Human Frontier Science Program Young Investigator, and Kimmel Scholar for Cancer Research.
Robert D. Gregg IV, Ph.D.University of Texas at Dallas
Project Title: Phase-Based Control of Locomotion for High-Performance Prostheses and Orthoses
Grant ID: DP2-HD-080349
Robert D. Gregg IV received the B.S. degree in electrical engineering and computer sciences from the University of California, Berkeley in 2006 and the M.S. and Ph.D. degrees in electrical and computer engineering from the University of Illinois at Urbana-Champaign in 2007 and 2010, respectively. He joined the Departments of Bioengineering and Mechanical Engineering at the University of Texas at Dallas (UTD) as an Assistant Professor in June 2013. Prior to joining UTD, he was a Research Scientist at the Rehabilitation Institute of Chicago and a Postdoctoral Fellow at Northwestern University. His research concerns the control mechanisms of bipedal locomotion with application to wearable control systems, including powered prostheses and orthoses. Dr. Gregg is a recipient of the NIH Director’s New Innovator Award, the Career Award at the Scientific Interface from the Burroughs Wellcome Fund, and the 2009 O. Hugo Schuck Award from the IFAC American Automatic Control Council.
Scott B. Hansen, Ph.D.The Scripps Research Institute
Project Title: Molecular Mechanism of Mechanosensation
Grant ID: DP2-NS-087943
Tracey J. Lamb, Ph.D.Emory University School of Medicine
Project Title: The Development of Probiotic Yeast as an Inexpensive Vaccine Delivery Platform
Grant ID: DP2-AI-112242
Julius B. Lucks, Ph.D.Cornell University
Project Title: A New High-Throughput Technology to Reveal the Dynamic Functional States of RNAs
Grant ID: DP2-GM-110838
Julius B. Lucks is Assistant Professor of Chemical and Biomolecular Engineering at Cornell University. His research combines both experiment and theory to ask fundamental questions about the design principles that govern how RNAs fold and function in living organisms, and how these principles can be used to engineer biomolecular systems. As a Miller Fellow, he pioneered the development of the first RNA-based synthetic genetic circuits, and was the leader of the team that created SHAPE-Seq – a technology that uses next generation sequencing to characterize RNA structures in unprecedented throughput, and that is now being used to uncover the role of RNA structure in regulating fundamental cellular processes across the genome. His lab focuses on dynamically programming cellular behavior with synthetic RNA circuitry, and using/developing SHAPE-Seq to understand RNA folding dynamics in the cell. For his pioneering research efforts, he has been named a DARPA Young Faculty Awardee, an Alfred P. Sloan Foundation Research Fellow, an ONR Young Investigator, an NIH New Innovator, and has been named an NSF CAREER awardee.
Linsey C. Marr, Ph.D.Virginia Tech
Project Title: The Role of Pathogen-Environment Interactions in the Pandemic Potential of Influenza
Grant ID: DP2-AI-112243
Linsey Marr is a professor of Civil and Environmental Engineering at Virginia Tech. Her research group studies the emissions, transformation, transport, and fate of air pollutants. She is especially interested in emerging or non-traditional aerosols such as engineered nanomaterials and viral pathogens. She received a B.S. in Engineering Science from Harvard College and a Ph.D. in Civil and Environmental Engineering from the University of California at Berkeley. She completed postdoctoral training in Earth, Atmospheric, and Planetary Sciences at the Massachusetts Institute of Technology.
Houra Merrikh, Ph.D.University of Washington School of Medicine
Project Title: Targeted Gene Evolution via Replication-Transcription Conflicts
Grant ID: DP2-GM-110773
Houra Merrikh received her Ph.D. in Molecular and Cellular Biology from Brandeis University in 2009. Her Ph.D. work focused on DNA damage responses in E. coli. She was a NIH postdoctoral fellow at the Massachusetts Institute of Technology from 2009 until 2011, where she studied DNA replication in B. subtilis. Upon completion of her postdoctoral training in Alan Grossman’s lab at MIT, she initiated her own research program at the University of Washington Medical School. Dr. Merrikh’s research is focused on understanding how impediments to DNA replication, such as transcription, impact the structure of the replisome, general physiology, genomic instability, and evolution in bacteria.
Ali Mortazavi, Ph.D.University of California Irvine
Project Title: Comparative Analysis of the 4D Encoding of Regulatory Networks in Stem Cells
Grant ID: DP2-GM-111100
Ryan M. O’Connell, Ph.D.University of Utah
Project Title: Utilizing TALEN Technology to Regulate Human microRNAs
Grant ID: DP2-GM-111099
Ryan O’Connell is an Assistant Professor at the University of Utah in the Department of Pathology. His postdoctoral studies were performed in David Baltimore’s laboratory at the California Institute of Technology where he began working in the area of microRNAs following his graduate training in Immunology at UCLA. Dr. O’Connell’s research has been focused on studying the roles of microRNAs in regulating both physiological and pathological hematopoietic development in mammals, with a focus on inflammation and cancer. Over the past decade his work has contributed significantly to our current understanding of the importance of microRNAs during the development, function and transformation of immune cells. Dr. O’Connell is currently working towards a further understanding of how microRNAs and other types of noncoding RNAs regulate inflammation and cancer, and exploring novel approaches to targeting this class of molecules to combat human disease.
Jukka-Pekka Onnela, Ph.D.Harvard University
Project Title: Using Mobile Phones for Social and Behavioral Sensing of Mood Disorder Patients
Grant ID: DP2-MH-103909
Jukka-Pekka “JP” Onnela is an Assistant Professor in the Department of Biostatistics at the Harvard T.H. Chan School of Public Health. His research focuses on statistical network science with applications to social and biological networks. His other main research area is digital phenotyping, the moment-by-moment quantification of the individual-level human phenotype using data from digital devices. Dr. Onnela was previously a Postdoctoral Research Fellow at Harvard Medical School, a Fulbright Visiting Scholar at the Harvard Kennedy School, and a Junior Research Fellow at Oxford University. He obtained his doctorate in network science at the Helsinki University of Technology in 2006.
Christian Petersen, Ph.D.Northwestern University
Project Title: Regulatory Circuits Controlling Regenerative Growth
Grant ID: DP2-DE-024365
Shelly Peyton, Ph.D.University of Massachusetts
Project Title: Tissue-Specific Stem Cells and Breast Cancer Tissue Tropism
Grant ID: DP2-CA-186573
Shelly Peyton was born in Coffeyville, Kansas. She received her B.S. in Chemical Engineering from Northwestern University in 2002, where she worked in the lab of Annelise Barron on surface chemistry for the human genome project. She received her Ph.D. in Chemical Engineering from the University of California, Irvine and worked for Andrew Putnam on how tissue stiffness contributes to smooth muscle pathology during atherosclerosis. Her postdoctoral research was at MIT, co-advised with Linda Griffith and Doug Lauffenburger in Biological Engineering, where she designed scaffolds to accelerate stem cell motility into wound sites for tissue regeneration. She is currently Assistant Professor of Chemical Engineering at the University of Massachusetts, Amherst. The Peyton lab engineers designer synthetic tissues to understand how cell-microenvironment interactions contribute to disease.
Vanessa Ruta, Ph.D.Rockefeller University
Project Title: Connecting Neural Plasticity to Learning and Memory
Grant ID: DP2-NS-087942
Ozgur Sahin, Ph.D.Columbia University
Project Title: Novel Sub-Cellular Chemical and Mechanical Nanoimaging
Grant ID: DP2-EB-018657
Ozgur Sahin is an Associate Professor of Biological Sciences and Physics at Columbia University. His research group is investigating energy conversion in biological nanostructures, developing nanomechanical approaches to determine structures of biomolecular complexes, and studying cell mechanics. Dr. Sahin is recognized for inventing a nanoscale microscope that can visualize mechanical properties of molecules, cells, and materials, for which he won the Grand Prize at the Collegiate Inventors Competition. He received a Junior Fellowship from the Rowland Institute at Harvard and a Packard Fellowship from the David & Lucile Packard Foundation.
Shomyseh Sanjabi, Ph.D.The J. David Gladstone Institutes
Project Title: Characterizing HIV Latent Reservoir In Vivo
Grant ID: DP2-AI-112244
Shomyseh Sanjabi is an assistant investigator at the Gladstone Institute of Virology and Immunology and the Roddenberry Center for Stem Cell Biology and Medicine, and an assistant professor in the department of Microbiology and Immunology at the University of California, San Francisco (UCSF). She earned a bachelor’s degree in microbiology and molecular genetics from the University of California, Los Angeles (UCLA) in 1997. She earned her Ph.D. in microbiology, immunology and molecular genetics in 2003 from UCLA working with Dr. Stephen Smale on molecular mechanism of NFk-B family member specificity. She was a recipient of Cancer Research Institute Postdoctoral Fellowship and did her postdoctoral training in immunobiology at Yale University with Dr. Richard Flavell studying the role of TGF-β signaling in CD8+ T cell biology. As a junior faculty, she has been the recipient of Hellman Family Career Faculty Award, Creative and Novel Ideas in HIV Research Award, and NIH Director’s New Innovator Award. Her laboratory studies mucosal anti-viral immunity, to better understand the mechanisms and factors that govern the innate and adaptive immune responses in the female reproductive tract and the rectum, the portals of viral entry during sexual viral transmission
Elizabeth Sattely, Ph.D.Stanford University
Project Title: Liberation of Plant Nutrients by the Gut Microbiota
Grant ID: DP2-AT-008321
David Savage, Ph.D.University of California, Berkeley
Project Title: Fluorescent Biosensors for Metabolite Imaging in Live Cells
Grant ID: DP2-EB-018658
Dave Savage is an Assistant Professor of Biochemistry, Biophysics, and Structural Biology in the Departments of Molecular & Cell Biology and Chemistry at the University of California, Berkeley. He was previously a graduate student in Biophysics with Robert Stroud at UCSF and a postdoctoral fellow with Pamela Silver at Harvard Medical School. His lab is broadly interested in microbial physiology and in developing new tools for the understanding and engineering of biology. For this work, he has been named an Alfred P. Sloan Foundation Research Fellow, a DOE Early Career Awardee, and a NIH New Innovator.
Marco Seandel, M.D., Ph.D.Weill Cornell Medical College
Project Title: Clonal Competition in Stem Cells as a Driver of Paternal Age Effect Diseases
Grant ID: DP2-HD-080352
Dr. Marco Seandel is an Assistant Professor of Cell and Developmental Biology in Surgery at Weill Cornell Medical College. Dr. Seandel received his M.D./Ph.D. from the State University of New York at Stony Brook, completed his internal medicine residency at New York-Presbyterian/Weill Cornell Medical Center and his medical oncology fellowship at Memorial Sloan Kettering Cancer Center. His lab is keenly interested in the mechanisms by which monogenic and complex disorders become increasingly prevalent in children as a function of the father’s age at the time of conception. He uses adult spermatogonial stem cells in vitro, stem cell transplantation, human genomics, and mouse models to understand the origin and mechanisms of human disease.
Sivaraj Sivaramakrishnan, Ph.D.University of Michigan
Project Title: The Kinase Toolbox: Mapping the Spatial and Temporal Regulation of Cell Signaling
Grant ID: DP2-CA-186752
Derek J. Taylor, Ph.D.Case Western Reserve University
Project Title: Induction of Cancer Cell Death by Selective DNA Misincorporation
Grant ID: DP2-CA-186571
Derek Taylor grew up in southwestern Colorado and attended Fort Lewis College where he received a B.S. in Chemistry and Cell and Molecular Biology. After working for two years in the Pharmaceutical Industry, Derek entered graduate school at the University of California, San Diego. Derek's Ph.D. thesis focused on molecular virology and macromolecular structure and function. As a postdoctoral fellow, Derek's research concentrated on understanding ribosome dynamics and the molecular mechanism of protein synthesis. To do so, he used cryo-electron microscopy to determine the structure of release and elongation factors bound to the eukaryotic ribosome. As an Assistant Professor, Derek's research has continued with the overall theme of understanding nucleoprotein complexes at a molecular level. His lab currently works on telomeres and telomerase.
Anna D. Tischler, Ph.D.University of Minnesota Medical School
Project Title: High-Throughput Identification of Mycobacterium tuberculosis Persistence Mechanisms
Grant ID: DP2-AI-112245
Anna Tischler is an Assistant Professor in the Department of Microbiology and Immunology at the University of Minnesota, where her lab focuses on persistence mechanisms of the bacterial pathogen Mycobacterium tuberculosis. She received a B.A. with high honors in Biology from Swarthmore College in 1999 and completed her Ph.D. training in Molecular Microbiology at Tufts University in 2005. During her graduate training with Dr. Andrew Camilli, Dr. Tischler identified the novel cyclic dinucleotide second messenger c-di-GMP as an important regulator of biofilm formation and virulence in the bacterial pathogen Vibrio cholera, the causative agent of cholera. As a post-doctoral fellow in the lab of Dr. John McKinney, she identified a Mycobacterium tuberculosis phosphate-sensing signal transduction system that is critical for bacterial evasion of host adaptive immune responses. Her lab is continuing to study this phosphate-sensing system and to elucidate other mechanisms that M. tuberculosis uses to persist in immune-competent hosts using bacterial genetics, animal models of infection, and high-throughput sequencing technologies.
Kay M. Tye, Ph.D.Massachusetts Institute of Technology
Project Title: A Novel Strategy for Combating Obesity: Reprogramming Neural Circuits
Grant ID: DP2-DK-102256
Kay Tye joined the faculty at MIT as an assistant professor in 2012, and is a member of the Picower Institute for Learning and Memory. Her lab is interested in understanding the neural circuits that allow us to assign positive or negative emotional valence to environmental stimuli. Perturbances in these circuits could give rise to a wide range of pathological states including anxiety, depression and addiction or compulsive overeating. She received her B.S. at MIT, her Ph.D. at UCSF and conducted her postdoctoral work at Stanford University. She has been recognized as as the recipient of the Harold Edgerton Faculty Achievement Award, was named one of TechReview's Top 35 Innovators Under 35, is a New York Stem Cell Foundation Neuroscience Robertson Investigator, a NARSAD Young Investigator and a McKnight Scholar.
Richard White, M.D., Ph.D.Memorial Sloan Kettering Cancer Center
Project Title: Evolutionary Dynamics of Melanoma Metastasis
Grant ID: DP2-CA-186572
Richard White is a physician-scientist using the zebrafish to study basic mechanisms underlying cancer metastasis. He clinically trained in Internal Medicine at Yale-New Haven Hospital and Medical Oncology at the Dana Farber Cancer Institute/Massachusetts General Hospital. This was followed by a postdoctoral fellowship in Leonard Zon’s lab at Harvard Medical School, where he helped develop the zebrafish as a platform for studying melanoma genetics. His work as a postdoc also led to the development of the transparent casper strain, which enables high resolution in vivo imaging of tumor progression. In his laboratory at Memorial Sloan Kettering, he is using the zebrafish to investigate three core components of metastatic biology: 1) how do developmental lineage factors present in the cancer cell of origin impact metastatic capacity? 2) what factors in the microenvironment act as selection forces to promote or retard metastatic progression?, and 3) how does the genome of the cancer cell evolve over time and space during metastasis? The zebrafish is a unique platform for addressing these questions because its optical clarity allows for high-throughput, high-resolution in vivo assessment of cellular behavior, and is highly amenable to unbiased screening approaches. Prior work from his laboratory has demonstrated that fundamental mechanisms uncovered in zebrafish melanoma have direct applicability to the human disease. He ultimately aims to use the zebrafish to discover basic mechanisms of cancer cell metastasis in order to improve the management of patients with disseminated disease.
Wilson Wong, Ph.D.Boston University
Project Title: Synthetically Reengineered T cells as the Next Generation of Smart Cancer Therapy
Grant ID: DP2-CA-186574
Wilson Wong is an Assistant Professor in the Biomedical Engineering Department at Boston University, and a core member of the BU Biological Design Center. His lab is focused on developing synthetic biology tools in mammalian systems for cell-based immunotherapy. He received his B.S. degree in Chemical Engineering from UC Berkeley and Ph.D. degree in Chemical Engineering from UCLA under the guidance from Dr. James Liao. He did his postdoctoral work under the mentorship of Dr. Wendell Lim at UCSF and learned some immunology from Dr. Arthur Weiss.
Ying Zheng, Ph.D.University of Washington
Project Title: A Microfluidic Bone Marrow Niche for the Study of Hematopoiesis
Grant ID: DP2-DK-102258
Ying Zheng is an Assistant Professor in the Department of Bioengineering at the University of Washington. She received her B.S. in Engineering Thermophysics from University of Science and Technology of China in 2002, and Ph.D. in Biomedical Engineering of University of Michigan, Ann Arbor in 2008. Previously, Dr. Zheng worked as a postdoctoral research fellow at Cornell University with Abraham Stroock on vascular engineering and regeneration. Her laboratory is interested in understanding and building fundamental structure and functions for living tissue and organ systems.
Christopher D. C. Allen, Ph.D.University of California San Francisco
Project Title: Cellular Interactions in Asthma
Grant ID: DP2-HL-117752
Christopher Allen received his B.S. in Biology at MIT in 2001, and his Ph.D. in Biomedical Sciences at UCSF in 2007. For his doctoral studies he worked under the mentorship of Jason Cyster at UCSF, characterizing the mechanisms responsible for cell migration and selection within the germinal center, a critical site for antibody affinity maturation. Following completion of his Ph.D., he was then selected for an early opportunity to start his own research group as a faculty fellow in the Sandler Asthma Basic Research Center at UCSF. In 2012, he was selected for a faculty position at UCSF as an Investigator of the Cardiovascular Research Institute and an Assistant Professor in the Department of Anatomy. His basic research program focuses on the cellular immune response in asthma, using two-photon microscopy to visualize interactions among cells in the lungs as well as in lymphoid organs that ‘prime’ cells for immune responses in the respiratory tract, with an emphasis on the development and function of IgE antibodies that contribute to allergic responses.
Debra Auguste, Ph.D.The City College of New York
Project Title: Personalized Therapeutics for Inhibiting Breast Cancer Metastasis
Grant ID: DP2-CA-174495
Emily Balskus, Ph.D.Harvard University
Project Title: Biocompatible Chemistry for In Vivo Metabolite Modification
Grant ID: DP2-GM-105434
Emily began her scientific career at Williams College, graduating in 2002, as valedictorian with highest honors in chemistry. After spending a year at the University of Cambridge as a Churchill Scholar in the lab of Prof. Steven Ley, she pursued graduate studies in the Department of Chemistry and Chemical Biology (CCB) at Harvard University, focusing on the development of asymmetric catalytic transformations and their application in the total synthesis of complex molecules under Prof. Eric Jacobsen and receiving her Ph.D. in 2008. From 2008–2011, Emily was an NIH postdoctoral fellow at Harvard Medical School in the lab of Prof. Christopher T. Walsh where her research involved elucidating and characterizing biosynthetic pathways for the production of small molecule sunscreens by photosynthetic bacteria. She also received training in microbial ecology and environmental microbiology as a member of the Microbial Diversity Summer Course at the Marine Biology Lab at Woods Hole during the summer of 2009. Emily joined Harvard’s CCB faculty in 2011, and she is currently an Associate Professor leading a research group interested in problems found at the intersection of chemistry and microbiology.
Trever G. Bivona, M.D., Ph.D.University of California San Francisco
Project Title: Discovery of Rational Companion Therapeutic Targets to Optimize Cancer Treatment
Grant ID: DP2-CA-174497
Dr. Trever Bivona is a board-certified medical oncologist with a Ph.D. in cell and molecular biology. He maintains an active academic clinical practice while also leading a basic and translational research laboratory focused on cancer genetics and precision medicine. A major research interest is enhancing the understanding of the molecular basis of targeted cancer therapy response and resistance. He leads a multi-disciplinary team of investigators in laboratory-based, patient-focused investigation and is a principal investigator on clinical trials, enabling a bench-to-bedside multi-faceted research program. The overall goal of these efforts is to improve survival in molecular subclasses of cancer patients through novel precision medicine approaches.
Josh L. Bonkowsky, M.D., Ph.D.University of Utah
Project Title: Trans-Cellular Activation of Transcription to Analyze Dopaminergic Axon Reorganization
Grant ID: DP2-MH-100008
Josh Bonkowsky, M.D., Ph.D., is an associate professor of Pediatric Neurology at the University of Utah. After his undergraduate training at Harvard University, Dr. Bonkowsky received a Fulbright Fellowship to Vienna, Austria, before his medical and Ph.D. training at the University of California, San Diego. Dr. Bonkowsky then moved to the mountains of Utah to do his clinical residency training in pediatrics and pediatric neurology at the University of Utah. Since 2006, he has been on faculty at the University of Utah, where he cares for patients with neurological disorders, and studies the mechanisms of nervous system development. His particular interests are studying how connections in the brain are formed, both during normal development, as well as when affected by diseases such as prematurity. His Innovator award focuses on a key problem in development of the brain- the necessity for accurate and precise connections- and developing a new method for visualizing and manipulating those connections.
Elhanan Borenstein, Ph.D.University of Washington
Project Title: A Computational Framework for Designing Microbiome Manipulation
Grant ID: DP2-AT-007802
Elhanan Borenstein is an Associate Professor of Genome Sciences at the University of Washington, with an adjunct position in the Department of Computer Science and Engineering. He is also an external professor at the Santa Fe Institute for complexity science. Dr. Borenstein received his Ph.D. in computer science from Tel-Aviv University, Israel, and held a joint postdoctoral fellowship at the Department of Biology in Stanford and at the Santa Fe Institute. He additionally has extensive professional experience in the hi-tech industry, where he held top management positions in several hi-tech companies. Dr. Borenstein is the recipient of various awards including the Alfred P. Sloan Fellowship and the NIH New Innovator Award. Dr. Borenstein integrates metagenomic data with methods inspired by systems biology, network theory, machine-learning, and statistical inference to develop a variety of computational methods for studying the human microbiome. His work focuses on reconstructing predictive, systems-level models of the human microbiome and on integrative, multi-meta-omic analysis, aiming to provide a better principled understanding of the microbiome and its role in human health. For more information visit http://elbo.gs.washington.edu/.
Cliff Brangwynne, Ph.D.Princeton University
Project Title: Cell Growth Control by Cell and Organelle Size-Dependent Ribosome Biogenesis
Grant ID: DP2-GM-105437
Cliff Brangwynne received a B.S. in Materials Science and Engineering from Carnegie Mellon University in 2001, and his Ph.D. in Applied Physics in 2007, from Harvard University, working in the group of David Weitz. He was a visiting fellow at the Max Planck Institute for the Physics of Complex Systems in Dresden, and was a Helen Hay Whitney Postdoctoral Fellow in the group of Tony Hyman at the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden. He is currently an assistant professor in the Department of Chemical and Biological Engineering at Princeton University. His research group uses tools and concepts from soft matter physics to study the assembly, properties and function of living matter. Their work has revealed that membrane-less organelles represent condensed liquid-like states of RNA and protein, which assemble by a type of intracellular phase transition.
Amy Hitchcock Camp, Ph.D.Mount Holyoke College
Project Title: A Feeding Tube Model for Bacterial Cell-Cell Communication
Grant ID: DP2-GM-105439
Amy Hitchcock Camp is an Assistant Professor in the Department of Biological Sciences at Mount Holyoke College. She received her A.B. in Molecular Biology at Princeton University and her Ph.D. in Biological Chemistry and Molecular Pharmacology at Harvard Medical School. During her graduate research under the supervision of Dr. Pamela Silver, she investigated the ubiquitination of membrane proteins at the endoplasmic reticulum. Following a year as a Visiting Assistant Professor at Mount Holyoke College, Dr. Camp was a Helen Hay Whitney Postdoctoral Fellow in the laboratory of Richard Losick at Harvard University. Her research as a postdoctoral fellow and now as a principal investigator aims to identify novel mechanisms of gene regulation and cell-cell communication that drive bacterial differentiation. Dr. Camp is a recipient of the Harvard Medical School Hauser Teaching Award, NIH Academic Research Enhancement Award, and the NIH Director’s New Innovator Award.
Jan Carette, Ph.D.Stanford University
Project Title: Genetic Approaches to Discover Host Factors Critical to Dengue Virus Infection
Grant ID: DP2-AI-104557
Shuibing Chen, Ph.D.Weill Medical College of Cornell University
Project Title: Studying the Progression and Regression of Beta Cell Dysfunction in Type 2 Diabetes
Grant ID: DP2-DK-098093
Ping Chi, M.D., Ph.D.Sloan-Kettering Cancer Center
Project Title: An Integrative Approach to Target Lineage-Specific Oncogenic Transcription Factor
Grant ID: DP2-CA-174499
Ping Chi is an Assistant Member in the Human Oncology and Pathogenesis Program (HOPP), and an Assistant Attending Physician and the Geoffrey Beene Junior Faculty Chair in the Department of Medicine. She completed clinical training in internal medicine at the Brigham and Woman’s Hospital and Medical Oncology at Memorial Sloan-Kettering Cancer Center, and a concurrent postdoctoral training in epigenetics and chromatin biology in the C. David Allis’ lab at the Rockefeller University. Her current laboratory research focuses on understanding the genetic and epigenetic mechanisms of transcriptional activation of novel oncogenic transcripts and oncogenic transcription factors in solid tumor malignancies. Through mechanistic studies, she aims to identify novel therapeutic strategies to target oncogenic transcription factors and aberrant transcriptional activation of oncogenes. She also maintains an active academic clinical practice, leads early phase clinical trials and works with a multidisciplinary team to care for patients with melanoma and sarcomas, with the goal to expedite clinical translation of laboratory research.
Mark Churchland, Ph.D.Columbia University Health Sciences
Project Title: A Dynamical Systems Approach to Fundamental Questions in Neuroscience
Grant ID: DP2-NS-083037
Professor Churchland is an Assistant Professor in the Department of Neuroscience at Columbia University Medical Center. He is the co-director of the Grossman Center for the Statistics of Mind. He received his B.A. in mathematics and psychology from Reed College in Portland Oregon. He received his Ph.D. in neuroscience from the University of California San Francisco. His postdoctoral work was in the Neural Prosthetic Systems Laboratory at Stanford University. Professor Churchland’s laboratory focuses on how the brain controls voluntary movement.
Bianxiao Cui, Ph.D.Stanford University
Project Title: Engineering External Forces for Manipulating Cargo Transport in Live Neurons
Grant ID: DP2-NS-082125
Bianxiao Cui is an Assistant Professor of Chemistry at Stanford University. She received a B.E. degree from the University of Science and Technology of China, a Ph.D. degree in Physical Chemistry from the University of Chicago, and a postdoctoral training in biophysics with Prof. Steven Chu in Stanford University. Her main area of interest is to develop physical and chemical approaches to study biological processes in cells. In particular, she focuses on (1) developing vertical nanopillar-based electric and optic sensors for sensitive detection of cellular functions; (2) investigating the axonal transport process using optical imaging, magnetic and optical trapping, and microfluidic platform, (3) using optogenetic approach to investigate the temporal and spatial control of intracellular signaling pathways. Her research achievement is recognized by numerous awards and distinctions include NSF inspire award (2013), NIH New Innovator Award (2012), NSF CAREER award (2011), Packard Fellowships in Science and Engineering (2010), Hellman Scholar (2012), Searle Scholar Award (2009) and Dreyfus New Faculty award (2009).
Gautam Dantas, Ph.D.Washington University of St. Louis
Project Title: Metagenomic Engineering of Probiotic Bacteria to Improve Intestinal Colonization Dynamics and Relative Fitness
Grant ID: DP2-DK-098089
Gautam Dantas, Ph.D., is an associate professor in the Department of Pathology & Immunology, the Department of Biomedical Engineering, the Deparmtment of Molecular Microbiology, and the Center for Genome Sciences & Systems Biology, at Washington University School of Medicine. He received his Ph.D. in biochemistry from the University of Washington under the guidance of Dr. David Baker, and post-doctoral training in microbial genomics from Harvard Medical School under the guidance of Dr. George Church. Dr. Dantas’s research interests and training lie at the interface of microbial genomics, synthetic biology, systems biology, and computational biology. His current research focuses on understanding the evolution and exchange of antibiotic resistance amongst diverse microbial communities, on engineering improved probiotics to treat gastrointestinal disorders, and on engineering microbial catalysts to produce value chemicals such as biofuels. He is a recipient of the AAAS Newcomb Cleveland Prize, the Harvard University Certificate for Distinction in Teaching, the NIH Director’s New Innovator Award, the Kenneth Rainin Foundation Breakthrough Award, the Edward Mallinckrodt Jr. Foundation Scholar Award, and the Academy of Science – St Louis Innovator Award. More information can be found at the Dantas Lab website.
Duc S. Dong, Ph.D.Sanford-Burnham Medical Research Institute
Project Title: Unlocking Regenerative Potential through In Vivo Genetic Reprogramming
Grant ID: DP2-DK-098092
Emily B. Falk, Ph.D.University of Pennsylvania
Project Title: Can Neuroscience Dramatically Improve our Ability to Design Health Communications
Grant ID: DP2-DA-035156
Emily Falk is an Associate Professor of Communication at the University of Pennsylvania’s Annenberg School for Communication, with additional appointments in the Center for Cognitive Neuroscience, Department of Psychology, and Warren Center for Network Science. Prof. Falk employs methods drawn from communication science, neuroscience and psychology to traverse levels of analysis from individual behavior, to diffusion in group and population level media effects. In particular, Prof. Falk is interested in predicting behavior change following exposure to persuasive messages and in understanding what makes successful ideas spread (e.g., through social networks, through cultures). Prior to her doctoral work, Prof. Falk was a Fulbright Fellow in health policy, studying health communication in Canada. She received her bachelor’s degree in Neuroscience from Brown University, and her Ph.D. in Psychology from the University of California, Los Angeles (UCLA).
Adam Walter Feinberg, Ph.D.Carnegie-Mellon University
Project Title: Human Myocardium Engineered Using Developmentally-Inspired Protein Scaffolds
Grant ID: DP2-HL-117750
Adam Feinberg is an Associate Professor in the Departments of Biomedical Engineering and Materials Science & Engineering at Carnegie Mellon University. He received his bachelor’s degree in Materials Science & Engineering from Cornell University, his Ph.D. in Biomedical Engineering from the University of Florida and his postdoctoral training in the School of Engineering and Applied Science at Harvard University. Prof. Feinberg’s research is focused on bottom-up engineering of the extracellular matrix (ECM) to understand fundamental aspects of matrix assembly and mechanobiology and applying these systems to engineer 3D human tissues using developmental biology as an instructive template for scaffold design. In particular, he is building 2D and 3D fibronectin nanofiber scaffolds that mimic the ECM in the embryonic heart to drive myogenesis using stem cell derived human cardiomyocytes. Prof. Feinberg is a 2012 recipient of the National Institutes of Health Director’s New Innovator Award and a 2015 recipient of the National Science Foundation CAREER Award.
Harvinder Singh Gill, Ph.D.Texas Tech University
Project Title: Pollen Grains as Trojan Horses for Oral Vaccination
Grant ID: DP2-HD-075691
Andrew L. Goodman, Ph.D.Yale University
Project Title: Defining the Contribution of Interpersonal Microbial Variation to Drug Metabolism
Grant ID: DP2-GM-105456
Andy Goodman is an associate professor of Microbial Pathogenesis and a member of the Microbial Sciences Institute at Yale University. He received his undergraduate training in Ecology and Evolutionary Biology at Princeton University and his Ph.D. in Microbiology from Harvard Medical School. His lab is works to dissect the interactions between resident gut commensal bacteria and their human host and to understand how these processes determine microbiome composition, pathogen resistance, and drug metabolism.
Jeff Gore, Ph.D.Massachusetts Institute of Technology
Project Title: Early Warning Indicators of Tipping Points in Biological Systems
Grant ID: DP2-AG-044279
Jeff Gore is an Associate Professor in the Department of Physics at the Massachusetts Institute of Technology. His group uses laboratory microbial microcosms to explore the ecological dynamics of interacting populations. With the support of a Hertz Fellowship, Jeff received his PhD at the University of California, Berkeley working with Carlos Bustamante on single-molecule biophysics. As a Pappalardo Postdoctoral Fellow at MIT Jeff then switched into the field of systems biology, studying cooperation and cheating with Prof. Alexander van Oudenaarden. Jeff is an Allen Distinguished Investigator, Sloan Fellow, Pew Scholar in the Biomedical Sciences, NIH Pathways to Independence Awardee, and an NSF CAREER Awardee.
Xue Han, Ph.D.Boston University
Project Title: Light-Actuatable NanoRobots for Molecular Uncaging
Grant ID: DP2-NS-082126
Dr. Xue Han is a Peter Paul Career Development Assistant Professor of Biomedical Engineering at Boston University. Her lab is developing novel genetic, molecular, and optical neurotechnologies for better understanding of neurological and psychiatric diseases. The ultimate goal of her research is to discover novel biomarkers and to develop radical new treatment options for brain disorders. Dr. Han received her B.S. in Biophysics from Beijing University in 2000, and then a Ph.D. in Physiology from the University of Wisconsin-Madison in 2004. Her thesis work focused on the molecular mechanisms of synaptic transmission, after which she completed her postdoctoral training as a Helen Hay Whitney Fellow at Stanford and MIT developing novel optogenetic tools and strategies for precise neural circuit manipulations.
Daniel A. Heller, Ph.D.Memorial Sloan Kettering Cancer Center
Project Title: Transient Metabolite Detection for Single-Cell Metabolomics and Diagnostics
Grant ID: DP2-HD-075698
Daniel Heller is an Assistant Member at Memorial Sloan-Kettering Cancer Center and an Assistant Professor in the Department of Pharmacology at Weill Cornell Medical College. His work focuses on nanoscale technologies, including optical biosensors for cancer research and diagnosis, and targeted nanoparticles to treat metastatic cancer. Dr. Heller obtained a B.A. in history from Rice University in 2000 and a Ph.D. in chemistry from the University of Illinois in 2010, with Prof. Michael Strano. He completed a Damon Runyon Postdoctoral Fellowship in the laboratory of Prof. Robert Langer at the Koch Institute for Integrative Cancer Research at MIT. Dr. Heller is a 2012 recipient of the National Institutes of Health Director’s New Innovator Award and a 2015 Kavli Fellow.
John M. Higgins, M.D.Massachusetts General Hospital/Harvard Medical School
Project Title: Systems Biology of In Vivo Human Blood Cell Populations
Grant ID: DP2-DK-098087
John Higgins studies the in vivo dynamics of human disease processes by developing and applying mathematical and computational models that synthesize existing understanding of physiologic systems, measurements from the clinical laboratory, and patient histories from electronic medical records. His research seeks to reveal new fundamental insight into human physiology and apply those new insights to the earlier and more accurate diagnosis of disease. He has an undergraduate degree from Princeton University and worked for several years as a computer software engineer at The MathWorks, Vermeer Technologies, and Microsoft. He received an M.D. and S.M. from the Harvard-MIT Division of Health Sciences and Technology, trained as a resident in Clinical Pathology at Brigham and Women’s Hospital, and did post-doctoral research in Applied Mathematics at Harvard University. He is an Associate Professor in the Harvard Medical School Department of Systems Biology and a practicing Clinical Pathologist in the Massachusetts General Hospital Department of Pathology.
Laura A. Johnson, Ph.D.University of Pennsylvania
Project Title: Gene-Engineered Adoptive T Cell Immunotherapy of GBM
Grant ID: DP2-CA-174502
Laura Johnson did her Ph.D. in Molecular and Cellular Immunology, followed by a postdoctoral fellowship in tumor immunotherapy with Dr. Steven Rosenberg at the NCI. Dr. Johnson’s current research is focused on translating immunotherapy from the research bench into the clinic to treat patients with cancer. As tumors are derived from otherwise normal self-tissues, it can be difficult to direct and maintain an immune response against them. Identifying factors present in the tumor microenvironment that can suppress the immune response, and gene engineering receptor molecules on T cells, it is possible to redirect the immune response to destroy cancer. As Director of the Solid Tumor Immunotherapy Lab, and an Adjunct Assistant Professor at the University of Pennsylvania, Dr. Johnson is extending this type of treatment to patients with brain cancer and other solid tumors. This type of immune therapy has the potential to benefit patients with all types of cancer, and myriad other diseases.
Rahul M. Kohli, M.D., Ph.D.University of Pennsylvania
Project Title: Combating Bacterial Drug Resistance by Targeting the Enzymes of Evolution
Grant ID: DP2-GM-105444
Dr. Kohli is a biochemist and infectious diseases physician. He is an Assistant Professor and Scholar in Molecular Medicine at the University of Pennsylvania, with appointments in the Department of Medicine and the Department of Biochemistry and Biophysics. The chief objective of his research group is to study the dynamic nature of the genome by probing enzymes and pathways that diversify genomes, particularly at the immune-pathogen interface. The focus of his New Innovator Award is on targeting the enzymes that allow bacterial pathogens to diversify and escape antibiotic therapy. His lab’s work has more broadly garnered support from the Rita Allen Foundation, the Doris Duke Foundation, the Edward J. Mallinckrodt Jr. Foundation, the Harrington Discovery Institute and the Burroughs Wellcome Fund.
Daniel Kronauer, Ph.D.Rockefeller University
Project Title: Studying the Molecular Mechanisms of Social Life Using a Novel Ant Model System
Grant ID: DP2-GM-105454
Daniel Kronauer studies social evolution and behavior within complex societies, using ants as model systems. He received his diploma in biology from the University of Würzburg in Germany in 2003, where he studied the evolution of social parasitism in honeypot ants with Bert Hölldobler and Jürgen Gadau. He received his Ph.D. in 2007 from the University of Copenhagen in Denmark, where he worked with Koos Boomsma on social dynamics in army ants. After a brief postdoctoral assignment at the University of Lausanne, he was elected as a junior fellow to the Harvard Society of Fellows in 2008, and joined The Rockefeller University as assistant professor in 2011. Daniel Kronauer is a 2012 Searle Scholar, a 2013 Kavli Fellow, a 2013 Hirschl/Weill-Caulier Trusts Research Award recipient, a 2014 Klingenstein-Simons Fellow in the Neurosciences, a 2015 Sinsheimer Scholar, and a 2015 Pew Biomedical Scholar.
Björn F. Lillemeier, Ph.D.Salk Institute for Biological Studies
Project Title: Decipher Membrane Patterns In Situ with Super-Resolution and Dynamic Microscopy
Grant ID: DP2-GM-105455
Björn F. Lillemeier received his M.S. in Biochemistry from the Free University of Berlin (Germany), and his Ph.D. in Biochemistry from Cancer Research UK (London; UK). He conducted his Postdoctoral research in immunology at Stanford University. In 2009, he joined the Salk Institute for Biological Studies as an Assistant Professor in the Nomis Center for Immunobiology and Microbial Pathogenesis and the Waitt Advanced Biophotonics Center. He currently studies the molecular assembly and spatial organization of signaling pathways in the plasma membrane during T cell antigen recognition and activation. To this end, he uses an array of multidisciplinary approaches that range from single molecule microscopy in live cells to determining structural and biochemical characteristics of proteins. The overall goal of the Lillemeier laboratory is to identify ‘check-points’ in signaling pathways that are based on novel principles and can be used to modulate cellular responses for future therapies.
Allen P. Liu, Ph.D.University of Michigan at Ann Arbor
Project Title: Building Artificial Platelets
Grant ID: DP2-HL-117748
Allen Liu studied Biochemistry as an undergraduate at University of British Columbia and worked for a year in a liposome biotechnology lab. During his Ph.D. work in Biophysics at UC-Berkeley with Dr. Daniel Fletcher, he developed an in vitro model system to study the dynamic interplay between actin network assembly and membrane organization and deformation. As a post-doctoral fellow in Cell Biology in Drs. Sandy Schmid and Gaudenz Danuser’s labs, he worked on understanding the heterogeneity of clathrin-coated pit dynamics using a combination of single live cell imaging and computational image analysis. In 2012, Liu established his own research group at University of Michigan in the Department of Mechanical Engineering, focusing on mechanobiology of biological membrane in relation to endocytosis, cell migration, and bottom-up synthetic biology.
Wendy Liu, Ph.D.University of California Irvine
Project Title: Engineering Biomaterials to Exert Molecular Control of Immune Cell Function
Grant ID: DP2-DE-023319
Gaby Maimon, Ph.D.Rockefeller University
Project Title: Linking Genes to Higher Brain Function by Way of Cellular Electrophysiology
Grant ID: DP2-DA-035148
Dr. Maimon received his undergraduate degree from Cornell University and his Ph.D. in neuroscience from Harvard University in 2005, working in the laboratory of John Assad. As a graduate student, he studied the neuronal basis for the action initiation in primate parietal cortex. He conducted his postdoctoral training from 2005 to 2010, at the California Institute of Technology with Michael Dickinson. As a postdoc, he studied how flies decide which way to fly based on the nature of the objects in their environment. He also developed the first method for recording electrophysiological signals from single neurons in tethered, flying fruit flies. He joined The Rockefeller University as assistant professor in 2011, and his lab continues to study the neuronal basis for behavior in fruit flies, as a model for understanding how brains perform fundamental computations, more generally.
Luciano A. Marraffini, Ph.D.Rockefeller University
Project Title: Using CRISPR Immunity to Prevent the Spread of Virulence Traits Among Pathogens
Grant ID: DP2-AI-104556
Luciano Marraffini performed doctoral work at the University of Chicago and post-doctoral studies at Northwestern University. Since 2010, he is an Assistant Professor and Head of the Laboratory of Bacteriology at The Rockefeller University. He is a pioneer in the study of prokaryotic adaptive immunity conferred by CRISPR-Cas loci, discovering that these immune systems target invading DNA molecules. His research focuses on understanding the molecular mechanisms of CRISPR-Cas immunity and its role in the control of horizontal gene transfer between bacteria. Dr. Marraffini has received numerous awards, including the Searle Scholars Award, the Rita Allen Foundation Award and was selected as a Finalist for the 2015 Blavatnik National Awards for Young Scientists. For more information about Dr. Marraffini, visit http://marraffini.rockefeller.edu.
Wei Min, Ph.D.Columbia University New York Morningside
Project Title: Label-Free Chemical Imaging for Biological Applications
Grant ID: DP2-EB-016573
Dr. Wei Min graduated from Peking University, China, with a Bachelor's degree in 2003. He received his Ph.D. in Chemistry from Harvard University in 2008, studying single-molecule biophysics with Prof. Sunney Xie. After continuing his postdoctoral work in Xie group, Dr. Min joined the faculty of Department of Chemistry at Columbia University in 2010. Dr. Min's current research interests focus on developing novel optical spectroscopy and microscopy technology to address biomedical problems. His contribution has been recognized by a number of honors, including Camille Dreyfus Teacher-Scholar Award (2015), George Fraenkel Fund Award (2014), Alfred P. Sloan Research Fellowship (2013), NIH Director's New Innovator Award (2012) and Faculty Finalist of Blavatnik Awards for Young Scientists of the New York Academy of Sciences (2012).
Sua Myong, Ph.D.University of Illinois Urbana-Champaign
Project Title: Quantitative Stepwise Analysis of RNA Interference
Grant ID: DP2-GM-105453
Sua Myong is an Associate Professor in Biophysics department at Johns Hopkins University. She has been trained in molecular cell Biology and biochemistry at UC Berkeley where she obtained both her undergraduate and graduate degrees. For her postdoctoral work, she joined Dr. Taekjip Ha (HHMI, University of Illinois) who pioneered single molecule fluorescence imaging techniques. Her research focuses on molecular understanding of biological pathways including RNA interference, DNA repair, recombination, telomere processing and nucleosome remodeling. Myong is a recipient of NIH New Director’s Innovator Award, American Cancer Society Research Scholar and Human Frontier Science Program Award.
Christopher Niell, Ph.D.University of Oregon
Project Title: Connecting Developmental Mechanisms to Visual Function and Perception
Grant ID: DP2-EY-023190
Axel Nimmerjahn, Ph.D.Salk Institute for Biological Studies
Project Title: Novel Approaches to Study Microglia Physiology and Pathology in the Intact Brain
Grant ID: DP2-NS-083038
Axel Nimmerjahn completed his Boehringer Ingelheim Fonds (B.I.F.)-supported Ph.D. in physics in the laboratories of Fritjof Helmchen and Bert Sakmann at the Max Planck Institute for Medical Research/University of Heidelberg, Germany. Following his Alexander von Humboldt and Human Frontier Science Program (HFSP)-supported postdoctoral training with Mark J. Schnitzer and Ben A. Barres at Stanford University he joined the faculty at the Salk Institute for Biological Studies in November 2010 as an assistant professor in the Waitt Advanced Biophotonics Center. His research focuses on elucidating the role of microglia - resident immune cells - and astroglia - key regulatory cells - in the healthy and diseased central nervous system through development of novel imaging tools and approaches. Nimmerjahn is recipient of a Du Bois-Reymond Award of the German Physiologic Society, Otto Hahn Medal and Award of the Max Planck Society, Scholar Award by the Rita Allen Foundation, and EUREKA Award by the NIH.
Sallie R. Permar, M.D., Ph.D.Duke University
Project Title: Maternal Immune Protection Against Congenital CMV Infection
Grant ID: DP2-HD-075699
Dr. Permar is a physician scientist focusing on the prevention and treatment of neonatal viral infections. She leads a research laboratory investigating maternal immune protection against vertical transmission of neonatal viral pathogens, including HIV and cytomegalovirus, using human cohorts and nonhuman primate models. Dr. Permar has a Ph.D. in Microbiology/Immunology from Johns Hopkins Bloomberg School of Public Health in Baltimore, an M.D. from Harvard Medical School and completed her clinical training in pediatric infectious diseases at Children’s Hospital in Boston. She is currently an Associate Professor in Pediatrics, and an Assistant Professor in Immunology and Molecular Microbiology and Genetics at Duke University Medical Center. Dr. Permar has made important contributions to the development of vaccines for prevention of infant HIV infection and the birth defects and neurologic deficits associated with congenital cytomegalovirus infection. She received several prestigious early-stage investigator awards, including the 2012 Presidential Early Career Award in Science and Engineering and the Society for Pediatrics Research Young Investigator Award in 2014.
Alexandrosc Pertsinidis, Ph.D.Sloan Kettering Institute for Cancer Research
Project Title: Understanding Gene Transcription from First-Principles: A Single-Molecule Study
Grant ID: DP2-GM-105443
Martin Prlic, Ph.D.Fred Hutchinson Cancer Research Center
Project Title: Paving the Way for a Novel Therapeutic Approach to Combat HIV
Grant ID: DP2-DE-023321
Martin Prlic is an Assistant Member in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center. He received his Master’s degree at the University of Salzburg, Austria, and his Ph.D. training in the Microbiology, Immunology and Cancer Biology Program at the University of Minnesota in the laboratory of Dr. Stephen Jameson. Martin’s thesis work focused on unraveling the mechanisms that control T cell and natural killer (NK) cell homeostasis. Following his training as a postdoctoral fellow in the laboratory of Dr. Michael Bevan, HHMI, at the University of Washington, Martin started his own laboratory at the FHCRC in 2011. His main goals are to understand how T cell, NK cell and MAIT cell fate and function are controlled in healthy, inflamed and infected tissues and identify how these cells can be manipulated for therapeutic purposes.
Avital Rodal, Ph.D.Brandeis University
Project Title: Activity-Dependent Regulation of Membrane Traffic and Growth Signaling in Neurons
Grant ID: DP2-NS-082127
Avital Rodal, Ph.D., is an Assistant Professor in the Biology Department at Brandeis University. Dr. Rodal received her Ph.D. in Molecular and Cell Biology from the University of California, Berkeley, where she studied the dynamics and ultrastructure of the yeast actin cytoskeleton in Dr. David Drubin's lab, and was an HHMI predoctoral fellow. She went on to do post-doctoral work at the Massachusetts Institute of Technology with Dr. Troy Littleton, investigating how developmental and cellular cues regulate neuronal growth and connectivity, and was the recipient of a Damon Runyon Postdoctoral award and the Charles King Trust of the Medical Foundation award. As a faculty member at Brandeis since 2010, she is the recipient of an NIH New Innovator Award, a Pew Scholar Award, an NIH Pathways to Independence Award, and a Basil O'Connor Scholar Award from the March of Dimes. Her research program focuses on how growth signals are mobilized and trafficked within neurons, and how manipulation of these dynamic trafficking events can be used in therapies to combat neurological disease.
Rajat Rohatgi, M.D., Ph.D.Stanford University
Project Title: Reconstructing Primary Cilia
Grant ID: DP2-GM-105448
Rajat Rohatgi M.D., Ph.D. is an assistant professor of Biochemistry and Medicine at the Stanford University School of Medicine. He graduated summa cum laude with an undergraduate degree in the Biochemical Sciences, where he worked on RNA biochemistry in Jack Szostak's lab. He then completed both M.D. and Ph.D. degrees at Harvard Medical School, working in Marc Kirschner's lab on signal transduction pathways that regulate actin assembly in cells. He finished clinical training in medicine and oncology at Stanford and completed a post-doctoral fellowship in Matt Scott's lab in the area of Hedgehog signal transduction. His laboratory works on the structure, assembly and signaling functions of the primary cilium, micron-scale signaling organelle that projects from most cells in our bodies and is required for the detection and processing of optical, chemical and mechanical signals.
Anne Schaefer, M.D., Ph.D.Mount Sinai School of Medicine
Project Title: Cognate Microglia-Neuron Interaction and Its Role in Inflammation
Grant ID: DP2-MH-100012
Dr. Anne Schaefer M.D., Ph.D., is an Assistant Professor of Neuroscience and Psychiatry at the Friedman Brain Institute at Icahn School of Medicine at Mount Sinai, New York. She joined Mount Sinai to start her own laboratory in 2011, after completion of the postdoctoral studies at Dr. Paul Greengard's Laboratory at The Rockefeller University in New York. Dr. Schaefer’s research focuses on the epigenetic mechanisms of neurological disordes such as epilepsy, autism, and neurodegeneration. Recently her lab pioneered studies of the epigenetic control of microglia diversification and function. Dr. Schaefer has been awarded with a NARSAD Young Investigator Award, Cure Challenge Award, Seaver Autism Research Award, Harold and Golden Lamport Research Award, and was named a 2014 Kavli Frontiers of Science Fellow by the National Academy of Sciences (NAS).
Xiaokun Shu, Ph.D.University of California San Francisco
Project Title: New Principle-Based Technologies for Identifying Transient Protein Interactions
Grant ID: DP2-GM-105446
Xiaokun Shu is an Assistant Professor in the Department of Pharmaceutical Chemistry and Cardiovascular Research Institute at UC San Francisco. In 2007, Dr. Shu finished his Ph.D. in Physics at University of Oregon with Prof. Jim Remington. Then he did a postdoctoral fellowship in the Department of Pharmacology at UC San Diego with Prof. Roger Tsien. During postdoctoral training, Dr. Shu developed an infrared fluorescent protein tag and a genetically encoded tag for correlated fluorescence and electron microscopy. He is applying Physics, Chemistry and Engineering to develop technologies for biology and to use new technologies to answer biological questions.
Vikaas S. Sohal, M.D., Ph.D.University of California San Francisco
Project Title: Reverse Engineering the Prefrontal Microcircuit
Grant ID: DP2-MH-100011
Dr. Sohal studied Applied Mathematics at Harvard and Cambridge before completing his M.D. and Ph.D. degrees at Stanford. He stayed at Stanford for a psychiatry residency, during which he also worked with Karl Deisseroth using optogenetics to study the mechanisms and functions of brain oscillations. He is currently a faculty member in the Department of Psychiatry and Center for Integrative Neuroscience at the University of California, San Francisco. His laboratory seeks to combine experimental and theoretical approaches in order to understand the “big picture” of how circuits in the prefrontal cortex function, and how they go awry in psychiatric disorders such as schizophrenia and autism. He continues to see psychiatric outpatients for one half day each week.
David Stoltz, M.D., Ph.D.University of Iowa
Project Title: Airway Goblet Cells: Friend or Foe?
Grant ID: DP2-HL-117744
Ming Su, Ph.D.Northeastern University
Project Title: Enhanced Radiation Therapy with Nanoscale Frequency Modulators
Grant ID: DP2-EB-016572
Ming Su is an associate professor at Department of Chemical Engineering of Northeastern University. He received his Ph.D. in Materials Science and Engineering from Northwestern University in 2004, and worked as a Eugene P. Wigner Fellow at Oak Ridge National Laboratory for two years. He was on faculty of University of Central Florida and Worcester Polytechnic Institute before joining Northeastern in 2014. His research interest is nanomedicines, where he uses nanoparticles to detect multiple biomarkers, to enhance radiation therapy, to kill bacteria, and to find out fake drugs.
Alexander Eckehart Urban, Ph.D.Stanford University
Project Title: Genomic and Epigenomic Effects of Large CNV in Neurons from iPSC
Grant ID: DP2-MH-100010
Ilana B. Witten, Ph.D.Princeton University
Project Title: Therapeutic Plasticity: A Novel Paradigm for Treating Addiction
Grant ID: DP2-DA-035149
Ilana Witten is an assistant professor in the Neuroscience Institute and the Department of Psychology at Princeton University. She did her Ph.D. work in the laboratory of Dr. Eric Knudsen at Stanford University, investigating crossmodal integration and plasticity in barn owls. She subsequently did her postdoctoral research in the laboratory of Dr. Karl Deisseroth, where she worked on developing and applying optogenetic strategies to dissect the function of defined cell-types within reward circuits in rodents. Her lab applies electrophysiology, optogenetics, and imaging to understand how reward circuits mediate normal behavior, as well as how they dysfunction in mental disorders.
Kim A. Woodrow, Ph.D.University of Washington
Project Title: Nanomaterials for Engineering Protection in the Genital Mucosa
Grant ID: DP2-HD-075703
Andrew Yoo, Ph.D.Washington University School of Medicine in St. Louis
Project Title: MicroRNA and Neural Factor-Mediated Direct Reprogramming of Cell Fates
Grant ID: DP2-NS-083372
Andrew Yoo is an Assistant Professor in the Department of Developmental Biology at Washington University School of Medicine. He did his Ph.D. work in the laboratory of Dr. Iva Greenwald at Columbia University, followed by postdoctoral work with Dr. Gerald Crabtree at Stanford University. He has a long standing interest in understanding genetic pathways that specify cell fates during development, and currently studies the role of microRNAs in regulating the activity of chromatin remodeling complexes during neural development and conversion of non-neuronal cells into neurons. Dr. Yoo’s work is also supported by the awards from the Ellison Medical Foundation, the Edward J. Mallinckrodt Jr. Foundation and the Presidential Early Career Award for Scientists and Engineers.
Siyang Zheng, Ph.D.Pennsylvania State University- University Park
Project Title: Integration of Flexible Micro Spring Array and High Throughput Microfluidics for Obtaining Clinical Relevant Information from Circulating Tumor Cells
Grant ID: DP2-CA-174508
Siyang Zheng is currently an associate professor of Biomedical Engineering at Pennsylvania State University. He received B.S. in Biological Science and Biotechnology from Tsinghua University, and Ph.D. in Electrical Engineering from California Institute of technology while studying miniaturized blood count technologies. He established the Penn State Micro & Nano Integrated Biosystem (MINIBio) Laboratory since 2009 focusing on developing innovative micro and nano technologies, applying these technologies to study complicated biological systems, and providing engineering solutions to current and future healthcare. His recent work includes label-free enrichment system for circulating tumor cells and viruses, nanomaterial integrated device and systems for biomarker detection and innovative devices for in vivo applications.
Ann C. Zovein, M.D.University California San Francisco
Project Title: Engineering Human Endothelium for Hematopoietic Stem Cell Production
Grant ID: DP2-HL-117743
Ann Zovein M.D., is an Assistant Professor of Pediatrics and an Investigator in the Cardiovascular Research Institute at UCSF. Her basic science laboratory studies the biology of blood vessels, and in particular their role in blood stem cell development. Dr. Zovein received both her B.S. in biomedical engineering and medical doctorate from Boston University. She then trained at UCLA Mattel Children's Hospital in Pediatrics with sub-specialization in Neonatology. There she also obtained subsequent postdoctoral training in the Department of Molecular, Cell, and Developmental Biology at UCLA in the laboratory of Luisa Iruela-Arispe Ph.D. Her long term goals include combining her training in engineering, medicine, stem and developmental biology to address novel and challenging questions in the fields of vascular and stem cell biology; ultimately translating stem cell science for the treatment of cardiovascular and hematologic disease. More information can be found at the Zovein laboratory website at http://www.zoveinlab.com/.
Stephen G. Aller, Ph.D.University of Alabama at Birmingham
Project Title: Streamlined Structures of Human Integral Membrane Proteins at Atomic Resolution
Grant ID: DP2-OD-008591
Steve is an Associate Professor in the Center for Structural Biology and Dept. of Pharmacology & Toxicology at the University of Alabama at Birmingham (UAB). He received his Ph.D. in Molecular Biophysics and Biochemistry at Yale University, and in postdoctoral work at the Scripps Research Institute, he solved the first x-ray crystal structure of any mammalian ATP-Binding Cassette (ABC) transporter called P-glycoprotein which is a cause of multidrug resistance in chemotherapy. Achieving success in the x-ray crystallography of a mammalian membrane protein (MP) is still largely a "shot in the dark", but the probability of success can be improved using brute-force approaches such as conducting crystal trials of several orthologs as opposed to only pursuing the structure of a human MP specifically. Yet, of course, the human MPs are of the highest interest since many are the direct causes of human disease and they are targets for a large percentage of pharmaceutical drugs currently on the market. Steve's research focus is to better understand the molecular basis of human disease and treatments with atomic precision by streamlining the crystal structure-determination process and increase success rates. He is currently pursuing structures of several new ABC proteins not previously crystallized.
Aaron B. Baker, Ph.D.University of Texas at Austin
Project Title: Engineering Effective Revascularization Strategies for Ischemia in Disease States
Grant ID: DP2-OD-008716
Aaron Baker is an Assistant Professor of Biomedical Engineering and a Fellow of the Marion E. Forsman Centennial Professorship in Engineering at the University of Texas at Austin. He earned his B.S.E/M.S.E. degrees in Bioengineering from the University of Washington and his Doctoral degree from the Harvard-MIT Health Sciences and Technology Program. He is a fellow of the American Heart Association and served as an associate scientific advisor for Science Translational Medicine. Dr. Baker’s laboratory focuses on using multidisciplinary approaches to study the mechanisms of cardiovascular disease and the interactions of cancer with the vascular system. His recent research has included the development of novel therapies for treating peripheral vascular disease and the creation of in vitro platforms for performing high throughput drug screening that incorporate the biomechanical forces present in the body.
Maria Barna, Ph.D.Stanford University
Project Title: Specialized Ribosomes in Control of Gene Expression and Embryonic Development
Grant ID: DP2-OD-008509
Maria Barna is an Assistant Professor in the Departments of Developmental Biology and Genetics at Stanford University. Dr. Barna obtained her B.A. in Anthropology from New York University and her Ph.D. from Cornell University, Weill Graduate School of Medicine. Dr. Barna was subsequently appointed as a UCSF Fellow through the Sandler Fellows program, which enables exceptionally promising young scientists to establish independent research programs immediately following graduate school. Her lab investigates an additional layer of gene regulation, termed a “ribocode”, whereby heterogeneity in composition enables ribosomes to be tuned to translate specific mRNAs. This research adds a fundamental new layer of gene regulation vital for post-transcriptional gene expression, organismal development, and evolution.
Uttiya Basu, Ph.D.Columbia University
Project Title: Non-Coding RNA Engineers Antibody Diversity
Grant ID: DP2-OD-008651
Uttiya Basu received his Ph.D. degree in Molecular Biology from Albert Einstein College of Medicine in 2004. After finishing postdoctoral training in the laboratory of Dr. Frederick Alt at Harvard Medical School in 2009, he joined Columbia University as an Assistant Professor in the Department of Microbiology and Immunology. His laboratory utilizes technologies involving genome engineering, genomics and biochemistry. His research is focused on the various mechanisms by which non-coding RNA transcription controls genome architecture in pluripotent and differentiated mammalian cells.
Nicolas E. Buchler, Ph.D.Duke University
Project Title: Rewiring the Yeast Brain: Redundancy and Interference in Genetic Networks
Grant ID: DP2-OD-008654
Nicolas Buchler is an Assistant Professor in the Department of Biology with a secondary appointment in Physics. He obtained his doctoral degree in Biophysics from the University of Michigan, where he worked with Richard Goldstein on protein designability and evolution. This was followed by postdoctoral research on the mechanisms and dynamics of gene regulation with Terence Hwa at the University of California, San Diego and then Frederick Cross at the Rockefeller University. Nick joined the Duke faculty in 2009. His lab uses an interdisciplinary approach (theory and experiment; physics and biology; synthetic and systems biology) to understand the diverse molecular and evolutionary mechanisms by which thresholds and combinatorial control, bistability and oscillation have evolved in biological systems.
Long Cai, Ph.D.California Institute of Technology
Project Title: Systems Biology in Single Cells by Super-Resolution Barcoding
Grant ID: DP2-OD-008530
Julie C. Canman, Ph.D.Columbia University
Project Title: IR-LAMP: Optigenetic Technology to Spatially Manipulate Protein Function In Vivo
Grant ID: DP2-OD-008773
Erin E. Carlson, Ph.D.University of Minnesota
Project Title: Targeted Natural Product Diversification to Identify Novel Antibacterial Agents
Grant ID: DP2-OD-008592
Erin E. Carlson is an Associate Professor in the Chemistry Department at the University of Minnesota and is appointed as a Graduate Faculty member of the Department of Medicinal Chemistry and the graduate program in Biomedical Informatics and Computational Biology. She received her B.A. at St. Olaf College and went on to graduate studies funded by the NIH Predoctoral Biotechnology Training Program at the University of Wisconsin - Madison and earned a Ph.D. in organic chemistry in 2005 under the direction of Professor Laura L. Kiessling. Subsequently, Dr. Carlson was awarded an American Cancer Society Postdoctoral Fellowship for studies at The Scripps Research Institute with Professor Benjamin F. Cravatt. In 2007, Dr. Carlson received an NIH Pathway to Independence Award (K99/R00) and started her independent career at Indiana University (2008-2014). Her research program unites tools from chemistry and biology to promote the development of new strategies for treatment of bacterial infections and the discovery of efficacious compounds.
Edward Chang, Ph.D.University of California, San Francisco
Project Title: Functional Architecture of Human Speech Motor Cortex
Grant ID: DP2-OD-008627
John T. Chang, M.D.University of California, San Diego
Project Title: Understanding the Basis for Cellular Diversity During Adaptive Immunity
Grant ID: DP2-OD-008469
John Chang is an Associate Professor of Medicine at the University of California, San Diego. He obtained his B.S. in Biological Sciences from Stanford University, his M.D. from Temple University, and research training as a Howard Hughes Medical Institute-National Institutes of Health Research Scholar in the laboratory of Dr. Ethan Shevach. Dr. Chang subsequently did his Internal Medicine residency and Gastroenterology fellowship at the University of Pennsylvania, completing a postdoctoral fellowship in immunology with Dr. Steven Reiner. Dr. Chang’s laboratory is focused on investigating basic immune mechanisms underlying lymphocyte fate determination in the context of infectious diseases and autoimmunity. Dr. Chang’s work has been recognized by an NIH Director’s New Innovator Award, a V Foundation for Cancer Research V Scholars Award, and a Howard Hughes Medical Institute Physician-Scientist Early Career Award.
Michelle C. Chang, Ph.D.University of California, Berkeley
Project Title: Discovery and Mechanistic Study of Fluorine Biochemistry
Grant ID: DP2-OD-008696
Wei Cheng, Ph.D.University of Michigan at Ann Arbor
Project Title: Single Cell With One Particle Entry (SCOPE) For Study Of HIV Infection
Grant ID: DP2-OD-008693
Dr. Cheng is an Associate Professor at the University of Michigan in the Department of Pharmaceutical Sciences and the Department of Biophysics. After earning a B.S. in biology from the University of Science and Technology of China, he completed his Ph.D. in the program of molecular biophysics in the Division of Biology and Biomedical Sciences at Washington University in St. Louis. After a postdoctoral training at UC-Berkeley, he accepted an endowed assistant professor position with the University of Michigan Ann Arbor in 2009. Professor Cheng’s lab develops single-molecule and single-particle techniques and applies them to fundamental questions in biology and disease, with a special focus on mechanisms of HIV infection.
Heather R. Christofk, Ph.D.David Geffen School of Medicine at the University of California, Los Angeles
Project Title: Regulation of the Warburg Effect in Cancer
Grant ID: DP2-OD-008454
Heather Christofk is an assistant professor in the Department of Molecular and Medical Pharmacology at UCLA and an affiliate of the Jonsson Comprehensive Cancer Center and the Broad Stem Cell Research Center at UCLA. Her research focuses on the regulation and role of metabolic switches in cellular transformation, virus infection, and differentiation. By elucidating regulatory mechanisms for metabolic switches in normal and disease states, she hopes to identify diagnostic and treatment strategies for cancer patients. Dr. Christofk received a bachelor’s degree in Molecular, Cell, and Developmental Biology from UCLA in 2001, and a doctorate in Cell and Developmental Biology from Harvard University in 2007, under the mentorship of Dr. Lewis Cantley. After a postdoctoral fellowship with Dr. Frank McCormick at UCSF, she joined the faculty at UCLA in 2008. In addition to the NIH Director’s New Innovator Award, Dr. Christofk is a Searle Scholar and has been awarded a Damon Runyon-Rachleff Innovation Award.
Hunter B. Fraser, Ph.D.Stanford University
Project Title: Systematic Functional Annotation of Human Cis-Regulatory Genetic Variation
Grant ID: DP2-OD-008456
Charles A. Gersbach, Ph.D.Duke University
Project Title: Engineering Morphogenetic Factors for Enhanced Genetic Reprogramming
Grant ID: DP2-OD-008586
Dr. Charles A. Gersbach is an Associate Professor at Duke University in the Departments of Biomedical Engineering and Orthopaedic Surgery, an Investigator in the Duke Center for Genomic and Computational Biology, and Director of the Duke Center for Biomolecular and Tissue Engineering. He received his Ph.D. from the Georgia Institute of Technology and completed postdoctoral training at The Scripps Research Institute. His research interests are in genome and epigenome editing, gene therapy, regenerative medicine, biomolecular and cellular engineering, synthetic biology, optogenetics, and genomics. Dr. Gersbach’s laboratory at Duke University is focused on applying molecular and cellular engineering to develop new methods to genetically modify genome sequences and cellular gene networks in a precise and targeted manner. Dr. Gersbach’s work has been recognized through awards including the NIH Director’s New Innovator Award, the NSF CAREER Award, and the Outstanding New Investigator Award from the American Society of Gene and Cell Therapy.
Aron M. Geurts, M.D., Ph.D.Medical College of Wisconsin
Project Title: Advanced Genetic Engineering Technology Development
Grant ID: DP2-OD-008586
Aron Geurts, Ph.D. received his training at the University of Minnesota–Twin Cities where he developed transposable element technology for gene therapy and mouse mutagenesis. He joined the Medical College of Wisconsin (Milwaukee) in 2006, and is currently an Associate Professor in the MCW Cardiovascular Center, Human Molecular Genetics Center, and the Department of Physiology where his laboratory pioneers and applies cutting edge gene editing approaches in stem cells and whole animals (primarily rats) to model human diseases including cardiomyopathies, mitochondrial diseases, hypertension, type 1 diabetes, and drug addiction. His lab is strongly motivated by the challenges of modeling human genetic variation and the practice of routinely applying gene editing toward Personalized Medicine. Dr. Geurts was awarded the New Innovator Award in 2011, supporting his efforts to advance genetic engineering technology.
Nathan C. Gianneschi, Ph.D.University of California, San Diego
Project Title: Programming Pharmacokinetics In Vivo via In Situ Switching of Nanoscale Particle
Grant ID: DP2-OD-008724
Nathan C. Gianneschi received his B.Sc.(Hons) at the University of Adelaide in 1999. In 2005, he completed his Ph.D. at Northwestern University. Following a Dow Chemical postdoctoral fellowship at The Scripps Research Institute in 2008, he became a professor at the University of California, San Diego. The Gianneschi group takes an interdisciplinary approach to nanomaterials research with a focus on multifunctional materials with interests that include biomedical applications, programmed interactions with biomolecules and cells, and basic research into nanoscale materials design, synthesis and characterization. For this work he has been awarded the NIH Director's New Innovator Award, the NIH Director's Transformative Research Award and the White House's highest honor for young scientists and engineers with a Presidential Early Career Award for Scientists and Engineers. Prof. Gianneschi was awarded a Drefus Foundation Fellowship, is a Kavli Fellow of the National Academy of Sciences, and is an Alfred P. Sloan Foundation Fellow.
Lea Goentoro, Ph.D.California Institute of Technology
Project Title: Relative Perception in Wnt Signaling
Grant ID: DP2-OD-008471
Lea Goentoro is an Assistant Professor in the Division of Biology and Biological Engineering at California Institute of Technology. She studied Chemical Engineering at University of Wisconsin, Madison, received Ph.D. from Princeton University, and conducted postdoctoral work in the Department of Systems Biology Department at Harvard Medical School. Her lab pursues the idea that just like our sensory systems perceive the world in a relative way, each cell in our body senses its environment in a relative manner. In her postdoctoral work with Marc Kirschner at Harvard Medical School, she observed experimental evidence for this in the canonical Wnt pathway, one of the major signaling pathways in animal cells. Funded by the New Innovator Award, her lab aims to uncover the mechanism for how cells compute the relative level of signal in the Wnt pathway, and explore how this computation is modified across tissues.
Ming C. Hammond, Ph.D.University Of California Berkeley
Project Title: A Chemical Biology Approach to Tagging RNAs in Live Cells
Grant ID: DP2-OD-008677
Songi Han, Ph.D.University of California, Santa Barbara
Project Title: Probing Early Protein Aggregation Mechanisms and Their Relationship to Disease Effects
Grant ID: DP2-OD-008702
Songi Han received her doctoral degree in natural sciences (Dr.rer.nat) from Aachen University of Technology (RWTH), Germany, in 2001. She pursued her postdoctoral studies at the University of California, Berkeley, supported by the Feodor Lynen Fellowship of the Alexander von Humboldt Foundation. She joined the faculty at UCSB in 2004, received tenure in 2010, and was promoted to full professor in 2012. At UCSB, she pioneered the direct measurement of water diffusivity and retardation at surface-water interfaces by Overhauser Dynamic Nuclear Polarization (ODNP), which has become important in soft matter solvent-function studies, and is being used to study a range of systems from bioinspired adhesive coacervate and fuel cell electrolyte transport studies to elucidating causal mechanisms in disease-prone globular and intrinsically disordered proteins. She is a recipient of the 2008 Packard Fellowship, the 2010 Dreyfus-Teacher Scholar Award, the 2011 NIH Innovator Award and the 2015 Bessel Prize of the Alexander von Humboldt Foundation.
Bo Huang, Ph.D.University of California, San Francisco
Project Title: Solving Macromolecular Complex Architecture In Situ by Super-Resolution Microscopy
Grant ID: DP2-OD-008479
Bo Huang received his B.S. degree in Chemistry from Peking University, China, in 2001, and Ph.D. degree in Chemistry at Stanford University in 2006. After finishing postdoc work at Harvard University in 2009, he joined UCSF as an Assistant Professor of in the Department of Pharmaceutical Chemistry, joint with the Department of Biochemistry & Biophysics, and was promoted to Associate Professor in 2014. His research work encompasses the areas of single molecule biophysics, microscopy, and cell biology. Being a pioneer in developing the super-resolution microscopy technique of STORM, he is currently interested in developing imaging new techniques for the study of genome organization, protein complexes and membrane receptors.
Christopher Hug, M.D., Ph.D.Children’s Hospital Boston / Harvard Medical School
Project Title: Macrophage Integrated and Targeted Yeast Therapeutics
Grant ID: DP2-OD-008618
Dr. Hug is a pediatric pulmonary physician and basic scientist. He received his B.S. and B.A. from the University of Cincinnati, M.D. and Ph.D. from Washington University in St. Louis, and completed medical training in pediatrics and pulmonary medicine at Boston Children's Hospital with post-doctoral research at the Whitehead Institute. His work advances the health of children and adults and involves collaborations spanning the globe but is centered at Boston Children's Hospital and Harvard Medical School, where he cares for children and young adults with lung disease. His research includes studies on diabetes and obesity, macrophage integrated and targeted yeast therapeutics, and global and environmental health.
Hongrui Jiang, Ph.D.University of Wisconsin, Madison
Project Title: Accomodative Contact Lens for Presbyopic Correction
Grant ID: DP2-OD-008678
Hongrui Jiang is currently the Lynn H. Matthias Professor in Engineering and the Vilas Distinguished Achievement Professor in the Department of Electrical and Computer Engineering, a Faculty Affiliate in the Department of Biomedical Engineering, a Faculty Member of the Materials Science Program, and a member of the McPherson Eye Research Institute, University of Wisconsin, Madison. He received the B.S. degree in physics from Peking University, Beijing, China, and the M.S. and Ph.D. degrees in electrical engineering in 1999 and 2001, respectively, from Cornell University, Ithaca, NY. He was a Postdoctoral Researcher at the University of California-Berkeley, Berkeley, from 2001 to 2002. His research interests are in optical MEMS, bioMEMS, smart materials and micro-/nanostructures, lab on a chip, and biomimetics and bioinspiration. Dr. Jiang was the recipient of numerous awards, including the NIH New Innovator Award, NSF CAREER Award, and DARPA New Faculty Award.
Sundeep Kalantry, Ph.D.University of Michigan Medical School
Project Title: Initiation of Epigenetic Transcriptional Regulation
Grant ID: DP2-OD-008646
Sundeep Kalantry is an assistant professor in the Department of Human Genetics at the University of Michigan Medical School. He received his Ph.D. from Weill Graduate School of Medical Sciences of Cornell University and performed a post-doctorate fellowship at UNC Chapel Hill with Terry Magnuson. Dr. Kalantry’s laboratory studies X-inactivation as well as other epigenetic processes that characterize the early embryo using mouse models. Dr. Kalantry is the recipient of an NIH Pathway to Independence Award (K99/R00), an NIH Director’s New Innovator Award (DP2), an Ellison Medical Foundation New Scholar in Aging Award, and a March of Dimes Basil O’Connor Starter Scholar Research Award.
Andrea M. Kasko, Ph.D.University of California, Los Angeles
Project Title: Phototunable Biomaterials to Engineer Complex 3D Cell Microenvironments
Grant ID: DP2-OD-008533
Andrea M. Kasko obtained a B.S. degree in Chemistry from the University of Michigan in 1997, a M.S.E degree in Macromolecular Science Engineering from Case Western Reserve University in 1999 (working with Virgil Percec), and Ph.D. in Polymer Science from the University of Akron in 2004 (working with Coleen Pugh). She spent two years as a post-doctoral researcher sponsored by the Howard Hughes Medical Institute at the University of Colorado, Boulder (working with Kristi Anseth). In 2006, Andrea joined the Bioengineering Department at UCLA, where she is currently an Associate Professor. The overall theme of her research group is the synthesis of new polymeric biomaterials, focusing specifically in two areas: dynamically controllable biomaterials and biomimetic and bio-derived materials.
Megan C. King, Ph.D.Yale University School of Medicine
Project Title: The Role of Nuclear Architecture in Adaptation
Grant ID: DP2-OD-008429
Megan King received her B.A. in Biochemistry from Brandeis University and her Ph.D. in Biochemistry and Molecular Biophysics from the University of Pennsylvania. During her postdoctoral training with Günter Blobel at Rockefeller University, she discovered new mechanisms for the targeting and function of integral inner nuclear membrane proteins. Since founding her own group in the Cell Biology Department at the Yale School of Medicine in 2009, Megan has continued to investigate the broad array of biological functions that are integrated at the nuclear envelope, from impacts on DNA repair to cellular mechanics. An ongoing goal is to understand how association of chromatin loci with the inner nuclear membrane influences genome integrity, particularly through regulation of homology-directed DNA repair. Megan was also named a Searle Scholar in 2011.
Steven T. Kosak, Ph.D.Northwestern University
Project Title: Self-Organization of the Human Genome
Grant ID: DP2-OD-008429
Steven T. Kosak is an assistant professor in the Department of Cell and Molecular Biology at Northwestern University Feinberg School of Medicine. He received his B.A. in Biology and English from Earlham College and his Ph.D. in Molecular Genetics and Cell Biology from The University of Chicago. As a graduate student he began his focus on the functional organization of the vertebrate genome. Dr. Kosak went on to pursue the relationship between gene regulation and nuclear organization as a Jane Coffin Childs Postdoctoral Fellow in the laboratory of Dr. Mark Groudine at the Fred Hutchinson Cancer Research Center. With his own group at Northwestern, Dr. Kosak continues to broadly examine how the human genome self-organizes in relation to its myriad functions.
Gyanu Lamichhane, Ph.D.Johns Hopkins University
Project Title: New Drug for Treatment of Chronic Bacterial Infection
Grant ID: DP2-OD-008459
Gyanu Lamichhane is an Associate Profession in the Division of Infectious Diseases, Johns Hopkins University. He started and runs a research program titled ‘Taskforce to study Resistance Emergence & Antimicrobial development Technology’ (TREAT) with a focus to discover vulnerabilities in bacterial pathogens and to leverage the biochemical properties of the vulnerabilities to develop new antimicrobials. His group currently studies metabolism of bacterial peptidoglycan and is working to exploit novel molecular vulnerabilities in the pathway of peptidoglycan biosynthesis. They have recently characterized L,D-transpeptidases, novel enzymes involved in the final step of peptidoglycan biosynthesis.
Seok-Yong Lee, Ph.D.Duke University School of Medicine
Project Title: Pharmacology and Biophysics of the Voltage-Gated Sodium Channel Nav1.7: A Therapeutic Target for Pain
Grant ID: DP2-OD-008380
Shaun W. Lee, Ph.D.University of Notre Dame
Project Title: Design and Use of Novel Bacteriocins
Grant ID: DP2-OD-008468
Shaun Lee is an Associate Professor at the University of Notre Dame in the Department of Biological Sciences, and an investigator in the Eck Institute for Global Health. He received his Ph.D. at Oregon Health and Science University in Molecular Microbiology and Immunology, under the direction of Dr. Maggie So, and completed postdoctoral training at University of California San Diego under the direction of Dr. Jack Dixon. Dr. Lee's research focuses on the biosynthesis and function of bacterially produced peptide compounds. Many of these compounds have been investigated for their roles in host virulence as well as microbial defense and signaling, and may uncover new avenues for developing therapeutics and antibiotic compounds.
Erez Lieberman Aiden, Ph.D.Harvard University / Broad Institute
Project Title: Exploring How the Genome Folds Through Proximity Ligation and Sequencing
Grant ID: DP2-OD-008540
Timothy Lu, M.D., Ph.D.Massachusetts Institute of Technology
Project Title: High-Throughput Nanoscale Approaches to Studying and Inhibiting Amyloid Toxicity
Grant ID: DP2-OD-008435
Timothy Lu, M.D., Ph.D. is an Associate Professor leading the Synthetic Biology Group in the Department of Electrical Engineering and Computer Science and the Department of Biological Engineering at MIT. He is a core member of the MIT Synthetic Biology Center and a co-founder of Sample6 Inc., Synlogic Inc., Eligo Biosciences, and Engine Biosciences. Tim’s research at MIT focuses on engineering computing and memory circuits in living cells, applying synthetic biology to tackle important medical and industrial problems, and building living biomaterials that integrate biotic and abiotic functionalities. He is a recipient of the NIH New Innovator Award, the Presidential Early Career Award for Scientists and Engineers, the Ellison Medical Foundation New Scholar in Aging Award, the ACS Synthetic Biology Young Investigator Award, and the Biochemical Engineering Journal Young Investigator Award, among others.
Emanual M. Maverakis, M.D.University of California, Davis / VA Northern California Health Care System
Project Title: Investigation and Development of New Therapeutic Avenues for Scleroderma
Grant ID: DP2-OD-008752
Douglas A. Mitchell, Ph.D.University of Illinois Urbana-Champaign
Project Title: A Common Denominator of Pathogenesis; a Rare Opportunity for Novel Therapeutic Development
Grant ID: DP2-OD-008463
Professor Mitchell received his undergraduate degree in chemistry from Carnegie Mellon University in 2002. After a short internship in medicinal chemistry at Merck Research Laboratories, he obtained his Ph.D. from the University of California, Berkeley in 2006. For postdoctoral studies, he worked with Jack Dixon at the University of California, San Diego. Professor Mitchell joined the University of Illinois faculty in 2009 and has research interests that span the interface of chemistry and biology. View his Twitter page.
Harald C. Ott, M.D., Ph.D.Massachusetts General Hospital
Project Title: Organ Engineering Based on Perfusion Decellularized Matrix
Grant ID: DP2-OD-008749
Timothy P. Padera, Ph.D.Massachusetts General Hospital
Project Title: Characterizing Lymphatic Micrometastases: Prognostic and Therapeutic Implications
Grant ID: DP2-OD-008780
Dr. Padera earned Bachelor of Science degrees in both Chemical Engineering and Biomedical Engineering from Northwestern University in 1997. He then received his PhD from MIT in 2003 in Medical Engineering from the Harvard-MIT Division of Health Sciences and Technology under the supervision of Rakesh K. Jain. He is currently Assistant Professor of Radiation Oncology at Harvard Medical School and the Massachusetts General Hospital as well as a Member of the Harvard-MIT Health Sciences and Technology Faculty. Dr. Padera is recognized as a leader in the field of intravital functional lymphatic imaging, particularly with respect to tumor growth, lymphatic metastasis and lymphatic vessel pumping. He has published seminal papers looking at the role of functional peritumor lymphatic vessels in tumor dissemination (Science 2002), the source of lymphatic dysfunction in tumors (Nature 2004) and the lack of angiogenesis in the growth of lymph node metastases (JNCI 2015). His New Innovator Award focuses on the role the lymph node microenvironment plays in protecting cancer cells from therapy and inhibiting anti-cancer immunity.
Brian M. Paegel, Ph.D.The Scripps Research Institute
Project Title: Evolving and Engineering New Protease Tools for Mass Spectrometry Proteomics
Grant ID: DP2-OD-008535
Brian M. Paegel is associate professor in the Department of Chemistry at The Scripps Research Institute. Paegel earned his undergraduate degree in chemistry from Duke University and his doctoral degree in chemistry from UC Berkeley. He pursued postdoctoral studies in chemical biology and molecular evolution at The Scripps Research Institute, where he was the recipient of both a NIH National Research Service Award and a Pathway to Independence Award. In 2008 he was appointed to the chemistry faculty and relocated to TSRI’s new east coast campus in South Florida where he received a NIH Director’s New Innovator award and a NSF CAREER award. He is interested in the assembly of cell-like compartments and the unique chemistry and biology that can be conducted in their confines. He studies cellular membrane assembly, evolution of new proteases for mass spectrometry-based proteomics, DNA-encoded compound library synthesis, and picoliter-scale compound screening.
Michael Petrascheck, Ph.D.The Scripps Research Institute
Project Title: Modulation of Sensory Perception to Treat Age Related Disease
Grant ID: DP2-OD-008398
Michael Petrascheck obtained his doctoral degree from the University of Zurich in the Institute of Molecular Biology. He then joined the Linda Buck at the Fred Hutchinson Cancer Research Center in Seattle to study aging in C. elegans using a chemical genetics approach. Screening thousands of compounds for those that extend C. elegans lifespan he has identified over hundred lifespan extending compounds. Elucidating some of the underlying mechanisms he has found that many of these compound act on the nervous system by blocking biogenic amine signals such as serotonin suggesting that modulating signals by the nervous system is sufficient to extend lifespan.
Christine Queitsch, Ph.D.University of Washington, Seattle
Project Title: Does Organismal Robustness Explain the Missing Heritability in Complex Diseases?
Grant ID: DP2-OD-008371
Christine Queitsch conducted her undergraduate studies at Martin-Luther-University Halle-Wittenberg. She received a Fulbright fellowship to study with Susan Lindquist and earned her Ph.D. in Molecular Genetics and Cell Biology at the University of Chicago. She continued her research as a Bauer Fellow at the FAS Center for Systems Biology at Harvard, before joining the faculty at the Genome Sciences department of the University of Washington, Seattle, where she is currently an Associate Professor. Christine’s research focuses on the genetic architecture of complex traits. She advances complex trait genetics by ascertaining uncharacterized sequence variation and by resolving the relative importance of additive variation and epistasis in complex traits. Her ultimate goal is the development of molecular markers, applicable in any organism, that predict the penetrance of genetic variants in a given individual.
Arjun Raj, Ph.D.University of Pennsylvania
Project Title: A Comprehensive Spatial Picture of Transcription in the Nucleus
Grant ID: DP2-OD-008514
Arjun Raj went to UC Berkeley, where he majored in math and physics, earned his Ph.D. in math from the Courant Institute at NYU and did his postdoctoral training at MIT before joining the faculty in Penn Bioengineering in 2010, where he is currently an assistant professor. His research focus is on the developed experimental techniques for making highly quantitative measurements in single cells and models for linking those measurements to cellular function. His ultimate goal is to achieve a quantitative understanding of the molecular underpinnings of cellular behavior.
Christian D. Schlieker, Ph.D.Yale University
Project Title: Deciphering Novel Protein Quality Control Pathways in the Nuclear Periphery
Grant ID: DP2-OD-008624
Christian Schlieker majored in Genetics and Biochemistry at the University of Bonn, earned his Ph.D. from the University of Heidelberg and worked as postdoctoral fellow at Harvard Medical School and the Whitehead Institute for Biomedical Research/MIT. He is now an associate professor in Molecular Biophysics & Biochemistry in Yale where he investigates molecular mechanisms underlying nuclear envelopathies.
David M. Tobin, Ph.D.Duke University
Project Title: Modulating Eicosanoids to Treat Tuberculosis: Personalized, Host-Directed Therapy
Grant ID: DP2-OD-008614
David Tobin, a 2011 New Innovator Awardee, is in the Departments of Molecular Genetics and Microbiology and Immunology at Duke University's School of Medicine. His research focuses on understanding genetic susceptibility to tuberculosis and the host immune response to mycobacterial infection. He trained as a graduate student with Cori Bargmann at the University of California, San Francisco and completed a postdoctoral fellowship with Lalita Ramakrishnan at the University of Washington. He is also a recipient of a Searle Scholar Award, a Mallinckrodt Scholar Award, an ICAAC Young Investigator Award, and a Vallee Foundation Young Investigator Award. Before beginning his postdoctoral fellowship, he lived and taught in Guatemala, where he continues to collaborate.
C. Jason Wang, M.D., Ph.D.Stanford University
Project Title: Healthy Ideas Exchange
Grant ID: DP2-OD-008647
Douglas B. Weibel, Ph.D.University of Wisconsin, Madison
Project Title: Revisiting the Bacterial Cell Wall as a Target for New Antibiotics
Grant ID: DP2-OD-008735
Douglas B. Weibel is an Associate Professor of Biochemistry, Chemistry, and Biomedical Engineering at the University of Wisconsin-Madison. He received his B.S. degree in chemistry in 1996, from the University of Utah, was a Fulbright Fellow at Tohoku University, Japan from 1996-1997, and received his Ph.D. in chemistry from Cornell University in 2002. During his graduate studies he spent two summer at Orchid Cellmark and the Max Planck Institute for Chemical Ecology, Jena, Germany. From 2002-2006 he was a postdoctoral fellow at Harvard University where his research spanned the fields of chemistry, materials science and engineering, and microbiology. From 2014-2015, Douglas was a visiting professor of physics at the University of Washington, Seattle and a principal scientist at Amazon.com, Inc.
Rebecca A. Wingert, Ph.D.University of Notre Dame
Project Title: Identification of Kidney Regeneration Mechanisms Using the Zebrafish
Grant ID: DP2-OD-008470
Joy Y. Wu, M.D., Ph.D.Massachusetts General Hospital
Project Title: In Vivo Reconstitution of the Hematopoietic Niche
Grant ID: DP2-OD-008466
Joy Wu is an Assistant Professor of Medicine in the Division of Endocrinology at the Stanford University School of Medicine. She received her M.D. and Ph.D. degrees from Duke University, followed by residency training in Internal Medicine at Brigham and Women’s Hospital and a clinical fellowship in Endocrinology, Diabetes and Metabolism at Massachusetts General Hospital. Her research focuses on skeletal development and the bone marrow hematopoietic niche, and her laboratory is using induced pluripotent stem cells to study osteoblast differentiation in a skeletal complementation model in vivo. In addition to the NIH Director’s New Innovator Award, she is the recipient of the Endocrine Scholars Award and Merck Senior Fellow Award from the Endocrine Society, the John Haddad Young Investigator Award from the American Society for Bone and Mineral Research, and a Cancer Research Grant from the Mary Kay Foundation.
Joao Xavier, Ph.D.Sloan-Kettering Institute for Cancer Research
Project Title: Engineering Microbial Social Interactions: Towards New Anti-Biofilm Therapies
Grant ID: DP2-OD-008440
Joao Xavier is a faculty member at Memorial Sloan-Kettering Cancer Center where he applies a combination of experiment and theory to investigate cell-cell interactions. Originally trained as a chemical engineer (IST Lisbon, 1998), Joao was fascinated by the emergence properties of biological systems and decided to pursue biofilm biology for his PhD (New University of Lisbon, 2003). After a first postdoc in biochemical engineering (Delft University of Technology, 2003-2005) he turned his attention to fundamental problems in evolutionary biology in a second postdoc with Kevin Foster at Harvard (2006-2009) to investigate the evolution of cooperation among bacteria. He started his lab at Sloan-Kettering in December 2009 and has since expanded his interests beyond biofilms to investigate other systems of medical relevance: the gut microbiota and cancer.
Qi Zhang, Ph.D.Vanderbilt University
Project Title: Explore Fundamental Aspects of Neurotransmission with Multifunctional Nanosensor
Grant ID: DP2-OD-008761
Haining Zhong, Ph.D.Oregon Health and Science University
Project Title: Examining the Architecture of Synapses in Brain Tissue at Nanometer Resolution
Grant ID: DP2-OD-008425
Haining Zhong is an assistant scientist at the Vollum Institute of Oregon Health & Science University at Portland, Oregon. He received a B.S. degree in biology and a B.Eng. degree in computer sciences from Tsinghua University, Beijing, China in 1996, and his Ph.D. degree from Johns Hopkins University School of Medicine in 2002, working with Dr. King-Wai Yau. He did his postdoctoral work with Drs. Karel Svoboda and Eric Betzig at HHMI Janelia Research Campus before joining Vollum in 2010. Haining’s research focus on examining neuronal function at the cellular and circuitry levels in vitro and in vivo using cutting-edge microscopic techniques. He also develops innovative solutions in sample preparation and labeling methods, which is required for successful application of microscopy to study biology in tissue.
Nathalie Y.R. Agar, Ph.D.Brigham and Women’s Hospital / Harvard Medical School
Project Title: Real-Time Stereotactic Mass Spectrometry Tissue Analysis for Intraoperative Neurosurgical Guidance
Grant ID: DP2-OD-007383
Ritesh Agarwal, Ph.D.University of Pennsylvania
Project Title: Optoelectronic Nanowire Probes for Investigation of Intracellular Processes
Grant ID: DP2-OD-007251
Rommie E. Amaro, Ph.D.University of California, Irvine
Project Title: A Structural Systems Biology Approach to Drug Discovery
Grant ID: DP2-OD-007237
Alexei Aravin, Ph.D.California Institute of Technology
Project Title: Taming of Small RNA-Based Epigenetic Mechanisms
Grant ID: DP2-OD-007371
Andrea M. Armani, Ph.D.University of Southern California
Project Title: Ultrasensitive Nanolasers for Epigenetics Investigations
Grant ID: DP2-OD-007391
Prof. Andrea Armani received her B.A. in physics from the University of Chicago (2001) and her Ph.D. in applied physics with a minor in biology from the California Institute of Technology (2007), where she continued as the Clare Boothe Luce post-doctoral Fellow in biology and chemical engineering. She is currently the Fluor Early Career Chair of Engineering and an Associate Professor of Chemical Engineering and Materials Science and Electrical Engineering-Electrophysics in the Viterbi School of Engineering at the University of Southern California. Prof. Armani’s research group focuses on the creation of polymeric and dielectric materials and the use of these materials to the fabrication of novel optical devices for understanding cancer progression.
Diana M. Bautista, Ph.D.University of California, Berkeley
Project Title: New Approaches to Identify Molecular Mechanisms of Touch and Pain in Mammals
Grant ID: DP2-OD-007123
Lynette S. Cegelski, Ph.D.Stanford University
Project Title: Structure, Function, and Disruption of Microbial Amyloid Assembly and Biofilm Formation
Grant ID: DP2-OD-007488
Jianjun Cheng, Ph.D.University of Illinois at Urbana-Champaign
Project Title: Developing Clinically Applicable, Cancer-Targeting Polymeric Nanoconjugates
Grant ID: DP2-OD-007246
Jianjun Cheng obtained a B.S. degree in Chemistry from Nankai University, China, in 1993, a M.S. degree in Chemistry from Southern Illinois University at Carbondale in 1996, and a Ph.D. degree in Materials Science from the University of California, Santa Barbara in 2001 with Professor Timothy Deming. He was a Senior Scientist at Insert Therapeutics, Inc. from 2001 to 2004, and a Postdoctoral Research Scientist at MIT with Professor Robert Langer from 2004 to 2005. He joined the Department of Materials Science and Engineering at the University of Illinois at Urbana-Champaign (UIUC) as a tenure-track Assistant Professor in 2005, and was promoted to Associate Professor in 2011 and to Full Professor in 2015. He is now developing new functional bionanomaterials for drug and gene delivery for cancer therapy and for cancer targeting.
Neil C. Chi, M.D., Ph.D.University of California, San Diego, School of Medicine
Project Title: Directed Cardiac Cellular Programming: A New Paradigm for Cardiac Regeneration
Grant ID: DP2-OD-007464
Adam Ezra Cohen, Ph.D.Harvard University
Project Title: Optical Sensing of Voltage, pH, and Small Molecules Using Microbial Rhodopsins
Grant ID: DP2-OD-007428
Adam Cohen is in the departments of Chemistry and Chemical Biology and Physics at Harvard and an investigator with the Howard Hughes Medical Institute. Current research in the Cohen Lab focuses on new approaches to imaging brain function. His work combines protein engineering, cell biology, advanced instrumentation, and development of computational methods.
Chengkai Dai, Ph.D.The Jackson Laboratory, Maine
Project Title: Role of a Novel Stress Response Mechanism-Genetic Buffering-in Tumor Evolution
Grant ID: DP2-OD-007070
Chengkai Dai received his medical and M.S. degrees from Tianjin Medical University, China. As a graduate student, he used mouse models to study gliomagenesis with Dr. Eric Holland at MD Anderson Cancer Center in Houston and Memorial Sloan Kettering Caner Center in New York. After earning his Ph.D. degree from The University of Texas Health Science Center Houston in 2003, he worked with Dr. Susan Lindquist at Whitehead Institute for Biomedical Research in Boston to study the role of the proteotoxic stress response in tumorigenesis. At the beginning of 2009, he joined The Jackson Laboratory in Bar Harbor as an Assistant Professor and his laboratory focuses on understanding proteomic instability of cancer. He received a Children’s Tumor Foundation Young Investigator Award in 2006, an Ellison Medical Foundation New Scholar in Aging Award in 2009, and a NIH Director’s New Innovator Award in 2010.
Sandeep Robert Datta, M.D., Ph.D.Harvard Medical School
Project Title: Revealing Fear: New Methods to Study Neural Circuits, Behavior, and Disease
Grant ID: DP2-OD-007109
Sandeep Robert Datta obtained a Bachelor of Science degree in Molecular Biochemistry and Biophysics from Yale University in 1993, and obtained an M.D./Ph.D degree from Harvard University in 2004. After working as a postdoctoral fellow at Columbia University with Richard Axel, he joined the Harvard Medical School Department of Neurobiology in 2009. His lab focuses on understanding how sensory cues — particularly odors — are detected by the nervous system, and how the brain transforms information about the presence of salient sensory cues into patterns of motivated action. This work involves studying genes involved in detecting odors, revealing the patterns of neural activity deep in the brain that encode sensory maps of the outside world, and probing the fundamental statistical structure of behavior itself. Dr. Datta has received the NIH New Innovator Award, the Burroughs Welcome Career Award in the Medical Sciences, the Alfred P. Sloan Research Fellowship, the Searle Scholars Award, the Vallee Young Investigator Award, the McKnight Endowment Fund Scholar Award and has been named a fellow of the National Academy of Science/Kavli Scholars program.
Dino Di Carlo, Ph.D.University of California, Los Angeles
Project Title: Engineering the Intracellular Micro- and Nanoenvironment
Grant ID: DP2-OD-007113
Dino Di Carlo is Professor in the department of Bioengineering at the University of California, Los Angeles. He received his B.S. in Bioengineering from the University of California, Berkeley in 2002, and received a Ph.D. in Bioengineering from the University of California, Berkeley and San Francisco in 2006. He then conducted postdoctoral studies from 2006-2008, at the Center for Engineering in Medicine at Harvard Medical School and Massachusetts General Hospital. He has made unique contributions across fields, uncovering fundamental microscale fluid physics, developing next-generation single-cell analysis tools, engineering microscale multifunctional materials and connecting cell physical properties to underlying disease. Among other honors he was awarded the National Science Foundation (NSF) Faculty Early Career Development award and the U.S. Office of Naval Research (ONR) Young Investigator Award in 2012, the Packard Fellowship for Science and Engineering and Defense Advanced Research Projects Agency (DARPA) Young Faculty Award in 2011, and received the Coulter Translational Research Award in 2010.
Alexander R. Dunn, Ph.D.Stanford University
Project Title: Uncovering New Roles for Mechanical Force in Tissue Development and Extracellular Matrix Remodeling
Grant ID: DP2-OD-007078
Conor L. Evans, Ph.D.Massachusetts General Hospital / Harvard Medical School
Project Title: Imaging and Overcoming Hypoxia-Induced Resistance in Metastatic Ovarian Cancer
Grant ID: DP2-OD-007096
Brian J. Feldman, M.D., Ph.D.Stanford University
Project Title: Using Components of the Circadian Clock to Regulate Stem Cell Fate Decisions
Grant ID: DP2-OD-006740
Dr. Feldman earned his M.D. and Ph.D. at Stanford Medical School. He then went on to complete his residency in Pediatrics at Children’s Hospital Boston, and served as a Pediatric Endocrinology postdoctoral fellow at the University of California, San Francisco. He returned to Stanford to open his independent laboratory as a faculty member in the Department of Pediatrics and Program in Regenerative Medicine. Dr. Feldman's research is investigating a number of aspects of hormone action that impact stem cell biology and stem cell fate decisions. In particular, he is developing tools based on hormonal signaling pathways that regulate circadian clock components in stem cells to modulate cell fate decisions in vivo in an attempt to generate novel therapeutics for a variety of diseases. In recognition of his innovative research, Dr. Feldman has been given numerous prestigious awards including the Lawson Wilkin’s Scholar Award from the Pediatric Endocrine Society, the Young Investigator Award from the Society of Pediatric Research, the Early Investigator Award from the Endocrine Society and the Bechtel Endowed Faculty Scholar Award.
M. Julia B. Felippe, D.V.M., Ph.D.Cornelll University College of Veterinary Medicine
Project Title: Epigenetics: A Novel Approach in Primary Immunodeficiencies
Grant ID: DP2-OD-007216
Julia Felippe is an associate professor at Cornell University College of Veterinary Medicine. Julia received her veterinary degree at Faculdade de Medicina Veterinaria e Zootecnia, University of Sao Paulo – UNESP, Botucatu, a Master of Science at Kansas State University, and a Ph.D. in immunology at Cornell University. Julia is board-certified by the American College of Veterinary Internal Medicine. She assists large animal patients at the veterinary hospital, and runs a clinical immunology laboratory that provides immunologic testing for horses. Her research program studies developmental immunology and immunodeficiencies, particularly common variable immunodeficiency (CVID) in horses. Current questions focus on epigenetic mechanisms of disease that can be applied to regenerative clinical intervention; for instance, reversing aberrant epigenetics in hematopoietic stem cells for the development and transplantation of autologous B cells in patients with humoral immunodeficiencies.
Michael A. Fischbach, Ph.D.University of California, San Francisco
Project Title: Identifying and Characterizing Small Molecules from the Human Microbiome
Grant ID: DP2-OD-007290
Michael Fischbach is an Associate Professor in the Department of Bioengineering and Therapeutic Sciences at UCSF and a member of the California Institute for Quantitative Biosciences (QB3). Fischbach is a recipient of the NIH Director's New Innovator Award, a Fellowship for Science and Engineering from the David and Lucille Packard Foundation, a Medical Research Award from the W.M. Keck Foundation, a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease award, a Glenn Award for Research in Biological Mechanisms of Aging, and the Young Investigator Grant for Probiotics Research from the Global Probiotics Council. His laboratory uses a combination of genomics and chemistry to identify and characterize small molecules from microbes, with an emphasis on the human microbiome. Fischbach received his Ph.D. as a John and Fannie Hertz Foundation Fellow in chemistry from Harvard in 2007, where he studied the role of iron acquisition in bacterial pathogenesis and the biosynthesis of antibiotics; before coming to UCSF, he spent two years as an independent fellow at Massachusetts General Hospital coordinating a collaborative effort based at the Broad Institute to develop genomics-based approaches to the discovery of small molecules from microbes. Fischbach is a member of the scientific advisory boards of NGM Biopharmaceuticals, Reckitt Benckiser, Symbiota, and Warp Drive Bio, and a member of Genentech's Scientific Resource Board.
Benjamin A. Garcia, Ph.D.Princeton University
Project Title: Novel Methodology for Quantitative High-Throughput Cancer Epigenetics
Grant ID: DP2-OD-007447
Thomas M. Guerrero, M.D., Ph.D.The University of Texas M.D. Anderson Cancer Center
Project Title: Spatially Accurate Deformable Image Registration for Thoracic CT Application
Grant ID: DP2-OD-007044
Monica L. Guzman, Ph.D.Cornell University Weill Medical College
Project Title: Selection of Novel Therapies to Ablate Chemoresistant Myeloid Leukemia Stem Cell
Grant ID: DP2-OD-007399
Amy Elizabeth Herr, Ph.D.University of California, Berkeley
Project Title: Towards High Throughput Proteomics: A Micro/Nanofluidic Framework for Blotless Western Technology
Grant ID: DP2-OD-007294
Amy E. Herr received her B.S. in Engineering & Applied Sciences from the California Institute of Technology (Caltech). As a Ph.D. student at Stanford University, she studied electrokinetic transport in and design of multi-dimensional separations, with Profs. Thomas Kenny and Juan Santiago. She then held a staff scientist position at Sandia National Laboratories, where she turned her focus to design of microfluidic immunoassays for clinical disease diagnostics and for life sciences tools with single cell resolution. Amy joined the Bioengineering Department at the University of California, Berkeley as an Assistant Professor (2007), where she now holds the Lester John & Lynne Dewar Lloyd Distinguished Professorship. Her laboratory employs approaches drawn from chemical, mechanical, and electrical engineering with strong foundations in materials science and analytical chemistry to advance measure tools for the "mathematization" of biology & medicine.
Julie C. Dunning Hotopp, Ph.D.University of Maryland School of Medicine
Project Title: Impact of Bacterial-Animal Lateral Gene Transfer on Human Health
Grant ID: DP2-OD-007372
Tony Jun Huang, Ph.D.Pennsylvania State University
Project Title: On-Chip Optofluidic Laser Scanning Confocal Microscope for Early Cancer Detection
Grant ID: DP2-OD-007209
Tony Jun Huang is a professor in the Department of Engineering Science and Mechanics at The Pennsylvania State University. He received his Ph.D. degree in Mechanical and Aerospace Engineering from the University of California, Los Angeles (UCLA) in 2005, and his B.S. and M.S. degrees in Energy and Power Engineering from Xi’an Jiaotong University, Xi’an, China, in 1996 and 1999, respectively. His research interests are in the fields of acoustofluidics, optofluidics, and micro/nano systems for biomedical diagnostics and therapeutics. He has authored/co-authored over 150 peer-reviewed journal publications in these fields. His journal articles has been cited more than 4400 times at Web of Science (h-index: 37). He also has 15 patents and invention disclosures. He is a fellow of American Institute for Medical and Biological Engineering (AIMBE), Institute of Physics (IoP), and Royal Society of Chemistry (RSC). His work have been recognized with awards and honors such as a 2010 National Institutes of Health (NIH) Director’s New Innovator Award, a 2011 Penn State Engineering Alumni Society Outstanding Research Award, a 2011 JALA Top Ten Breakthroughs of the Year Award, a 2012 Outstanding Young Manufacturing Engineer Award from Society for Manufacturing Engineering, a 2013 Faculty Scholar Medal from The Pennsylvania State University, a 2013 American Asthma Foundation (AAF) Scholar Award, and the 2014 IEEE Sensors Council Technical Achievement Award from The Institute of Electrical and Electronics Engineers (IEEE).
Yu Huang, Ph.D.University of California, Los Angeles
Project Title: Graphene Nanostructures as a New Platform for Ultrasensitive Multiplexed Biological Sensors
Grant ID: DP2-OD-007279
Professor Yu Huang receives her Ph.D. in physical chemistry from Harvard University and her B.S. in chemistry from University of Science and Technology of China. At UCLA she explores the unique technological opportunities that result from the structure and assembly of nanoscale building blocks. Focusing on the molecular level, she conducts research to unravel the fundamental principles governing nanoscale material synthesis and assembly; and utilizes such principles to design nanostructures and nanodevices with unique functions and properties to address critical challenges in electronics, energy science and biomedicine. Recognitions she received include the World’s Top 100 Young Innovators, Nano 50 Awards, the Sloan Fellowship, the PECASE, DARPA Young Faculty Award and the NIH New Innovator Award.
Michelle Khine, Ph.D.University of California, Irvine
Project Title: Shrink Induced Manufacturing Platform for Low-Cost Diagnostics
Grant ID: DP2-OD-007283
Michelle Khine is currently an Associate Professor of Biomedical Engineering, Chemical Engineering and Materials Science at UC Irvine. Michelle was recently appointed Director of Faculty Innovation at the Henry Samueli School of Engineering and as Director of BioENGINE (BioEngineering Innovation and Entrepreneurship) at the Institute for Innovation, at UC Irvine. Michelle received her B.S. and M.S. from UC Berkeley in Mechanical Engineering and her Ph.D. in Bioengineering from UC Berkeley and UCSF. She was the Scientific Founder of Fluxion Biosciences, Shrink Nanotechnologies, Novoheart, TinyKicks, and her STEM-outreach initiative, 100 Tiny Hands. Michelle was the recipient of the TR35 Award, named Forbes ’10 Revolutionaries’, by Fast Company Magazine as one of the '100 Most Creative People in Business' and by Marie‐Claire magazine as 'Women on Top: Top Scientist' and was recently inducted as a Fellow of AIMBE (American Institute of Medical and Biological Engineering).
Ophir D. Klein, M.D., Ph.D.University of California, San Francisco
Project Title: An Evolutionary-Developmental Approach to Stem Cells Using Teeth as a Model
Grant ID: DP2-OD-007191
Ophir Klein is the Larry L. Hillblom Distinguished Professor in Craniofacial Anomalies, Professor of Orofacial Sciences and Pediatrics, and Chair of the Divisions of Craniofacial Anomalies and Orthodontics at the University of California, San Francisco (UCSF). He is also the Medical Director of the UCSF Craniofacial Center and Director of the UCSF Program in Craniofacial Biology. Dr. Klein was educated at the University of California, Berkeley, where he earned a B.A. degree in Spanish Literature. He subsequently attended Yale University School of Medicine, where he received a Ph.D. in Genetics and an M.D. degree. He then completed residencies at Yale-New Haven Hospital in Pediatrics and at UCSF in Clinical Genetics. Work in Dr. Klein’s research group centers on organ development and regeneration, with a major focus on understanding the processes underlying craniofacial development and integrating evolutionary and developmental approaches.
Joshua A. Kritzer, Ph.D.Tufts University
Project Title: Drugging the Undruggable: Targeting Transcription Factors with Small Cyclic Peptides
Grant ID: DP2-OD-007303
Joshua Kritzer is an Associate Professor at Tufts University’s Department of Chemistry and a member of the Sackler School for Graduate Biomedical Studies. He received a Ph.D. in Biophysical Chemistry at Yale University and did postdoctoral research in genetics with Dr. Susan Lindquist at the Whitehead Institute. The Kritzer Lab targets disease-associated proteins that are “undruggable” via traditional means, using new strategies that cut across synthetic chemistry, biochemistry, biophysics, genetics and cell biology.
Diana J. Laird, Ph.D.University of California, San Francisco
Project Title: Cell Competition in the Developing Mouse Germline
Grant ID: DP2-OD-007420
Dr. Laird is an Associate Professor in the UCSF Department of Obstetrics, Gynecology and Reproductive Sciences and the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research. She received her Ph.D. in stem cell biology from Stanford with Irving Weissman and completed postdoctoral training in developmental genetics at Sloan Kettering Institute with Kathryn Anderson. She holds an A.B. in Physics from Harvard. Her research centers on the development of the gametes, with a focus on the genetic and epigenetic mechanisms in the embryo that determine the quantity of and quality of eggs or sperm in the adult. These endeavors are aimed toward understanding infertility, chromosomal abnormalities, and impact of environmental exposures on reproductive health.
Erin Lavik, Sc.D.Case Western Reserve University
Project Title: Clinically Translatable Nanotechnology: Hemostasis and Neuroprotection
Grant ID: DP2-OD-007338
Jin Hyung Lee, Ph.D.University of California, Los Angeles
Project Title: In Vivo Control and Functional Visualization of Stem Cell-Driven CNS Regeneration
Grant ID: DP2-OD-007265
Jin Hyung Lee is an Assistant Professor of Neurology and Neurological Sciences, Bioengineering, Neurosurgery, and Electrical Engineering (Courtesy) at Stanford University. Dr. Lee received her Bachelor’s degree from Seoul National University and Masters and Doctoral degree from Stanford University, all in Electrical Engineering. As an Electrical Engineer by training with Neuroscience research interest, her goal is to analyze, debug, and engineer the brain circuit through innovative technology.
Hara Levy, M.D.Northwestern University Feinberg School of Medicine and Ann and Robert H. Lurie Children’s Hospital
Project Title: Integration of Genomics with Genetics - Molecular Phenotypes for CF Lung Disease
Grant ID: DP2-OD-007031
The Levy lab focuses on integrating genetic and genomic analyses to advance our understanding of how environmental, genetic, and epigenetic factors influence the progression of CF. Although CF is a monogenic autosomal recessive disorder caused by mutations in the gene encoding cystic fibrosis transmembrane regulator (CFTR), clinical heterogeneity causes diagnostic uncertainty, especially in infants without symptoms and in older patients with milder phenotypes. A variety of genetic, epigenetic, and environmental factors further complicate the evolution of CF in each patient. For example, infection with the Gram-negative pathogen Pseudomonas aeruginosa accounts for most of the morbidity and mortality associated with lung disease in CF; we suspect that a set of immune proteins contributes to the severity of CF lung disease by mediating innate immunity to P. aeruginosa infection. Other changes in gene expression occur in CF, affecting fluid and electrolyte transport, intracellular trafficking, and inflammation. Thus, CF arises from the activities of genes and proteins within a complex transcriptional and functional framework. Global analyses are therefore critical to monitoring gene and protein expression and to understanding the mechanisms underlying the extensive phenotypic heterogeneity of CF. In the Levy lab, we use a novel approach to generate genome-wide expression profiles of CF patients over time. Molecular and cellular assays allow us to refine the mechanisms that underpin these changes in expression, and we are in the process of developing strategies to examine the expression of miRNAs and genes associated with single-nucleotide polymorphisms and/or copy-number variants. We anticipate that these investigations will highlight genes/proteins that define a patient’s clinical course and treatment response. Our clinical interests include establishing molecular definitions of disorders of the CF spectrum, such as CFTR-related diseases and CFTR-related metabolic syndrome, as well as exploring the impact of CFTR mutations on gene expression, predictors of lung-disease severity, newborn screening, and therapeutic responsiveness.
Ruth E. Ley, Ph.D.Cornell University
Project Title: Development of Immunization Strategies to Reshape Pathogenic Microbiomes
Grant ID: DP2-OD-007444
Minkui Luo, Ph.D.Memorial Sloan-Kettering Cancer Center
Project Title: Enzyme-Engineering Approaches to Dissect Protein Methylation Profiles
Grant ID: DP2-OD-007335
Minkui Luo obtained his B.S. degree in organic chemistry at Fudan University in 1999. He then traveled to the U.S. to pursue his Ph.D. in the field of bioorganic and bioinorganic chemistry under the guidance of Dr. John T. Groves, at Princeton. Then, in 2005, I joined the laboratory of Dr. Vern Schramm as a postdoctoral fellow at the Albert Einstein College of Medicine. In 2008, he started his independent career at the Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College (joint appointment). The current research in the Luo laboratory focuses on developing and implementing chemical tools to define, perturb and manipulate epigenetic functions of protein methyltransferases for disease diagnosis and therapy. Besides NIH New Innovator Award, Dr. Luo is also the recipient of ACS Eli Lilly Award of Biological Chemistry (2015), CTSC Novel Award (2014), Basil O'Connor Starter Scholar Award (2011), Alfred W. Bressler Scholar Award (2010), and the V Scholar Award for Cancer Research (2009).
Michael B. Major, Ph.D.University of North Carolina at Chapel Hill
Project Title: Exploitation of Near-Haploid Human Cells for Functional Gene Discovery
Grant ID: DP2-OD-007149
Ben Major is an assistant professor of Cell Biology and Physiology within the Lineberger Comprehensive Cancer Center at UNC-CH. He received his B.S. in microbiology from the Lyman Briggs College at Michigan State University where he worked on polyoma viruses in Michele Fluck’s laboratory. Ben received his Ph.D. in Oncological Sciences from the Huntsman Cancer Institute at the University of Utah. His graduate work in David Jones’ laboratory focused on the mechanics of TGF-b signaling in cancer models and in zebrafish. From there, Ben moved to Seattle for a post-doctoral position in Randall T. Moon’s laboratory where he helped develop proteomic and functional screening strategies to interrogate the WNT signaling pathway. Ben’s laboratory at UNC uses an integrative platform of mass spectrometry-based proteomics, functional genomics and computation to study how alterations in WNT and KEAP1/NRF2 signal transduction contribute to human disease.
John C. March, Ph.D.Cornell University
Project Title: Engineering Commensal Bacteria as Therapeutic Signal Mediators
Grant ID: DP2-OD-007155
Timothy J. Nelson, M.D., Ph.D.Mayo Clinic College of Medicine
Project Title: Dysfunctional Regeneration in Cardiomyopathy: iPS-Based Diagnosis and Therapy
Grant ID: DP2-OD-007015
Dr. Nelson earned his Ph.D. and M.D. from the Medical College of Wisconsin in Milwaukee, Wisconsin. His residency and fellowship work was done at Mayo Clinic in Rochester. He is currently an Associate Professor of Medicine and Director of the Todd and Karen Wanek Family Program for Hypoplastic Left Heart Syndrome at Mayo Clinic in Rochester. Dr. Nelson’s research work is focused on cardiovascular regeneration using bioengineered stem cells to improve the ability to discover, diagnose, and ultimately treat mechanisms of degenerative diseases such as cardiomyopathy. Building on expertise of embryology and cardiac developmental biology to study lineage specific defects in pluripotent stem cells, his research program is striving to translate innovative applications based on iPS technology into clinical applications in human diseases involving mitochondrial defects. This individualized platform allows for pharmacological-based screening efforts to identify novel therapeutic targets using patient-specific stem cell and differentiated derivatives.
Alexander B. Niculescu, M.D., Ph.D.Indiana University School of Medicine
Project Title: Developing Blood Tests for Mood Disorders
Grant ID: DP2-OD-007363
Jacquin C. Niles, M.D., Ph.D.Massachusetts Institute of Technology
Project Title: Engineered Regulated RNA Localization and Transport in Biological Systems
Grant ID: DP2-OD-007124
Elizabeth M. Nolan, Ph.D.Massachusetts Institute of Technology
Project Title: Antibacterial Peptides and Zinc in Innate Immunity and Mammalian Physiology
Grant ID: DP2-OD-007045
Elizabeth Nolan received her B.A. in Chemistry from Smith College, and she pursued her Ph.D. research under the guidance of Professor Stephen J. Lippard at the Massachusetts Institute of Technology. She was a NIH post-doctoral fellow with Professor Christopher T. Walsh at Harvard Medical School. She is currently an Associate Professor of Chemistry at the Massachusetts Institute of Technology. Her independent research focuses on the roles of transition metal ions in the host/microbe interaction with particular emphasis on metal-chelating human host-defense proteins as well as bacterial siderophores.
Manu O. Platt, Ph.D.Georgia Institute of Technology
Project Title: Multiscale, Mechanistic, and Predictive Models of Stroke in Sickle Cell Disease
Grant ID: DP2-OD-007433
Manu O. Platt received his B.S. in Biology from Morehouse College and his Ph.D. in Biomedical Engineering from the Georgia Institute of Technology and Emory University School of Medicine joint program studying endothelial cell biology and flow-mediated proteolytic remodeling during atherosclerosis progression under the mentorship of Dr. Hanjoong Jo. He then went onto postdoctoral training at MIT in orthopedic tissue engineering and systems biology with co-advisement by Dr. Douglas Lauffenburger and Dr. Linda Griffith. He began his independent career in January 2009, at the Coulter Dept of Biomedical Engineering at Georgia Tech/Emory, and is currently an associate professor. The Platt Lab studies proteolytic mechanisms in a number of diseases: pediatric strokes in children with sickle cell disease (for which his New Innovator was funded), HIV-mediated cardiovascular disease, and personalized medicine applications to predict individual patient-specific cancer metastasis potential.
Patrick Seale, Ph.D.University of Pennsylvania
Project Title: Molecular Regulation of Brown Adipose Cell Fate in Somitic Stem Cells
Grant ID: DP2-OD-007288
Balaji Sitharaman, Ph.D.State University of New York at Stony Brook
Project Title: Nanotechnology-Based Theranostic Technology for Bone Tissue Engineering
Grant ID: DP2-OD-007394
Luke S. Theogarajan, Ph.D.University of California, Santa Barbara
Project Title: Bio-Ionic Neural Interfaces
Grant ID: DP2-OD-007472
Budd A. Tucker, Ph.D.The University of Iowa Carver College of Medicine
Project Title: Development of a Cell Replacement Therapy to Treat Retinal Degenerative Blindness
Grant ID: DP2-OD-007483
Joseph Wade, Ph.D.Wadsworth Center, New York State Department of Health / University at Albany, State University of New York
Project Title: Pervasive Transcription in Bacterial Genomes
Grant ID: DP2-OD-007188
Joseph Wade is a Research Scientist at the Wadsworth Center, New York State Department of Health, and an Assistant Professor at the University at Albany, SUNY. Joe received his Ph.D. in Steve Busby’s group at the University of Birmingham, U.K. He then worked as a postdoctoral fellow in Kevin Struhl’s lab at Harvard Medical School. Joe’s group studies gene regulation in bacteria, with an emphasis on genome-scale approaches. Specific areas of interest include the impact of pervasive transcription in bacterial genomes, genomic analysis of transcription factor function, and regulatory networks associated with virulence in bacterial pathogens.
Lauren A. Weiss, Ph.D.University of California, San Francisco
Project Title: Dissecting Epistasis and Pleiotropy in Autism Towards Personalized Medicine
Grant ID: DP2-OD-007449
Pak Kin Wong, Ph.D.The University of Arizona
Project Title: Mechanoregulation of Tissue Morphogenesis
Grant ID: DP2-OD-007161
Pak Kin Wong is a Professor of Biomedical Engineering, Mechanical Engineering and Surgery at Pennsylvania State University. He was a faculty at the University of Arizona from 2006 to 2015. His laboratory develops advanced manufacturing strategies for elucidating mechanoregulation of collective cell migration in tissue regeneration and cancer metastasis and developing microfluidic systems for medical diagnostics. His group has established a nanoengineered systems framework, which combines bio fabrication of organotypic and 3D tissue models, nanoengineered probes for single cell gene expression analysis and ablation, biomechanical analysis of cell-cell and cell-matrix interaction, and agent-based computational modeling, for elucidating collective migration in tissue development and cancer metastasis. Among other honors, Dr. Wong was awarded the NIH Director's New Innovator Award in 2010, Arizona Engineering Faculty Fellow in 2011, AAFSAA outstanding Faculty Award in 2013, and JALA 10 – A Top 10 Breakthrough in Innovation in 2015.
Changhuei Yang, Ph.D.California Institute of Technology
Project Title: Applications of Time-Reverse Tissue Turbidity Suppression to Improve Biophotonics
Grant ID: DP2-OD-007307
Professor Yang's research efforts are in the areas of novel microscopy development and time-reversal based optical focusing. His group pioneered the Fourier Ptychographic imaging method that allows rendering of very high pixel count and large field of view microscopy images. His group also pioneered the use of wavefront engineering and phase conjugation methods to focus light deep within highly turbid biological tissues.
Peng Yin, Ph.D.Harvard University
Project Title: Engineering Bioimaging Probes Based on Triggered Molecular Geometry
Grant ID: DP2-OD-007292
Peng Yin is an Associate Professor of Systems Biology at Harvard Medical School and a Core Faculty Member at Wyss Institute for Biologically Inspired Engineering at Harvard University. He directs the Molecular Systems Lab at Harvard. His research interests lie at the interface of information science, molecular engineering, and biology. The current focus is to engineer information directed self-assembly of nucleic acid (DNA/RNA) structures and devices, and to exploit such systems to do useful molecular work. Such de novo designed systems are composed of small synthetic DNA/RNA monomers capable of conditional configuration change and can be programmed to self-assemble, move, and compute. They can serve as programmable controllers for the spatial and temporal arrangements of diverse functional molecules (e.g. fluorophores, proteins), with a wide range of applications in nano-fabrication, imaging, sensing, diagnostics, and therapeutics. See his work at http://molecular-systems.net.
Xilin Zhao, Ph.D.New Jersey Medical School-University of Medicine and Dentistry of New Jersey
Project Title: Anaerobic Shock as a Novel Treatment for Tuberculosis
Grant ID: DP2-OD-007423
Xilin Zhao is a principal investigator at the Public Health Research Institute (PHRI) and an Associate Professor in the Department of Microbiology, Biochemistry & Molecular Genetics at the New Jersey Medical School, Rutgers University. He obtained B.S. and M.S. training at Nankai University, China, and a Ph.D. from the John Innes Centre/University of East Anglia, UK. He worked with Karl Drlica at PHRI for more than a decade to develop the mutant selection window hypothesis, a framework for suppressing the emergence of antimicrobial resistance by adjusting dosing. He then opened his own lab at PHRI, which now addresses two new directions to better control bacterial infections. One program focuses on the live-or-die bacterial stress response to find new targets for small-molecule antimicrobial enhancers. The other program involves development of a novel, gas-based therapy for tuberculosis.
Sheng Zhong, Ph.D.University of California, San Diego
Project Title: Evolutionary Models for Gene Regulatory Networks
Grant ID: DP2-OD-007417
Sheng Zhong is an Associate Professor at the Department of Bioengineering, University of California San Diego. Sheng received a Ph.D. in Biostatistics from Harvard University. He worked at Stanford University as a visiting scholar and at University of Illinois at Urbana-Champaign as an assistant and an associate professor before moving to UC San Diego. His group studies gene regulation by developing both experimental and computational technologies. His lab discovered transposon-mediated re-wiring of transcription networks that govern mammalian embryonic development, and contributed to initiating "comparative epigenomics" - using cross-species epigenomic comparison to annotate the genomes.
Mark W. AlbersMassachusetts General Hospital
Project Title: The Olfactory Neural Circuit as a Systems Level Model of Neurodegenerative Diseases
Grant ID: DP2-OD-006662
Neurodegenerative disease will increasingly plague our society as modern medicine augments the number of people reaching their seventh, eighth, and ninth decades. These pathological processes erode the functional integrity of susceptible neural circuits. Much progress has been gained in identifying mutations and gene products that underlie these disease processes, particularly early onset Alzheimer's disease (AD) and Parkinson's disease (PD). While these findings have led to the development of mouse models of these diseases, little is known at the systems level about how these disease genes impact the function of a specific neural circuit. We have developed an experimental approach to elucidate the actions of genes that cause neurodegenerative disease in a single mammalian neural circuit. Using mouse genetics, we expressed an AD gene exclusively in primary olfactory sensory neurons in a conditional manner. Characterization of this model uncovered a population of mouse olfactory neurons that undergo enhanced cell death and axon mistargeting in a non-cell autonomous fashion in the presence of this AD gene. In this proposal, we outline a series of studies to extend our analysis of this mouse model by employing: 1) longitudinal in vivo functional imaging using multiphoton microscopy, and 2) primary olfactory neuron culture that can be adapted to high-throughput screens for molecules that reverse the cell death phenotype. Hits from this screen can be rapidly tested in the mouse model by intranasal delivery to the olfactory epithelium. In addition, we propose to extend this experimental approach to genes associated with other neurodegenerative diseases such as PD. Elucidation of the actions of these disease genes at a systems level with novel functional and cellular outcomes from our neural circuit mouse model and characterization of additional neurodegenerative disease genes in this model system hopefully will contribute to the development of effective therapies.
Adah AlmutairiUniversity of California, San Diego
Project Title: Chemically Amplified Response Strategies for Medical Sciences
Grant ID: DP2-OD-006499
A new, amplified response strategy for inducing multi-photon-driven processes noninvasively in living systems will be investigated. This strategy should enable optical and thus remote control or activation of substances inside living systems noninvasively, with a previously unattainable control of depth. The impact of such remote control is large and broad, allowing previously invasive procedures to be performed noninvasively, and previously inaccessible target sites to be reached for both treatment and diagnosis. Multi-photon phenomena allow unparalleled spatiotemporal control, and where longer wavelengths are employed, deeper penetration into turbid bulk media such as tissue. Despite the revolutionary impact these phenomena have had on neuroscience, microscopy, and lithography, it has been generally very difficult to apply this technique in vivo to stimulate biomaterials, diagnostics, and drug delivery systems. Currently there are no reported systems for in vivo multi-photon-responsive materials. The dogma is that not enough photons can reach the materials to initiate a response. The amplified response strategy we aim to explore is inspired by one that has revolutionized the electronics industry with the advent of chemically amplified photoresistors for the fabrication of computer chips. When a single responsive molecular unit, repetitively embedded in a material, simultaneously absorbs two photons, the changes in that molecular unit will cause the system to unravel entirely.
Euan A. AshleyStanford University
Project Title: Nanoscale Approaches to Allelic Silencing in Myocardial Disease States
Grant ID: DP2-OD-006511
Hypertrophic cardiomyopathy is the most common inherited cardiovascular disease. It affects one in 500 of the population. It is the most frequent cause of sudden death in young people. Despite groundbreaking work in defining the genetic basis for the disease, leading to the description of more than 400 predominantly missense mutations in more than 8 largely sarcomeric genes, therapies remain palliative. In this application, I outline an innovative approach to the treatment of the underlying genetic defect in hypertrophic cardiomyopathy. Dominant negative “poison peptide” transmission, together with a proof-of-principle phenotype reversal in a transgenic mouse model, provide the rationale. The combination of allele-specific RNA silencing and creative biological and physical approaches to cellular specificity provide the mechanism and route of delivery. Specificity provides the single greatest challenge, and I outline several innovative approaches to overcoming this. Potential translation to patients is a theme woven throughout the strategic plan. We begin with mutations identified in families from the Stanford Hypertrophic Cardiomyopathy Center; carry out basic RNA biology in an attempt to selectively silence these mutations in cell lines; and move progressively through organ models, then small animals, to a preclinical large animal model. The approach we outline is not limited to hypertrophic cardiomyopathy. The ability to selectively modify a single mutated allele and deliver the therapy in vivo could revolutionize the treatment of diverse genetic diseases and finally fulfill the therapeutic promise of the Human Genome Project. Finally, I argue that the most innovative ideas would never have been noticed without timing: With the genetic basis of the disease laid out, and many critical techniques on the verge of significant advancement, the time is right for a new approach.
Michel BagnatDuke University School of Medicine
Project Title: Discovering New Regulators of CFTR and Fluid Secretion in Zebrafish
Grant ID: DP2-OD-006486
Most internal organs are built around fluid-filled tubes, and control of fluid secretion is essential for their development and function. Defects in fluid secretion have been linked to some of the most prevalent genetic and acquired pathological conditions, including cystic fibrosis, polycystic kidney disease, and secretory diarrheas. At the cellular level, fluid secretion is driven by directional salt ion transport, which is then followed by water. Several key channels and pores responsible for ion and water transport have been identified. However, we still need to understand how fluid secretion functions as a developmental force and how different processes that depend on fluid secretion are coordinated at the whole-organism level. To address these fundamental problems, I have embarked on a fully integrated approach based on zebrafish genetics and physiology. My focus is on the cystic fibrosis transmembrane conductance regulator, a chloride channel that is the major regulator of fluid secretion in vertebrates. The proposed research plan will lead to new insights into: how fluid pressure shapes development and the responses elicited at the cellular level by this force, CFTR function, and how CFTR activity is regulated in vivo and in real time during development. We will also carry out a forward genetic screen to identify mutations controlling CFTR-dependent and -independent fluid secretion. These approaches will establish a new genetic and physiologic model system for studying the functional regulation and developmental potential of fluid secretion and CFTR activity.
Gábor BalázsiUniversity of Texas M.D. Anderson Cancer Center
Project Title: Connecting the Selection of Noisy Gene Expression Deviants to Genetic Evolution
Grant ID: DP2-OD-006481
Drug resistance of pathogenic cell populations causes the failure of therapy and represents a major challenge for today’s medicine. Early drug resistance has been shown to rely on intricate gene expression patterns across the cell population. However, current techniques of gene expression control (gene deletion, overexpression, knockdown, etc.) are aimed to control only the average gene expression across the cell population and are therefore insufficient to study how gene expression properties other than the mean affect drug resistance. This is creating a widening gap in knowledge, as we and others have recently demonstrated that gene expression characteristics other than the mean (such as the variance or cellular memory of deviant expression states) are just as important as the mean for cell population survival during drug treatment. Here we propose to develop novel, versatile, and modular gene constructs to control various expression characteristics of any gene in any organism. Negative feedback-based constructs will permit precise, linear inducer-dependent control of gene expression in every cell of the population. Positive feedback-based constructs will allow us to adjust the cellular memory (rate of stochastic expression fluctuations). We will use these constructs to control diverse expression characteristics of a drug-resistance gene and study how these expression properties affect cell survival during drug treatment and initiate the evolution of genetic drug resistance in a yeast cell population. We will develop multiscale, stochastic models to explain the mechanisms underlying the experimental observations. We can now directly visualize the expression of a drug resistance gene at the single-cell level. The innovation consists of bridging molecular- and cell-population dynamics and connecting stochastic gene expression fluctuations to genetic evolution in experiment and simulation. The results might transform our current understanding of drug resistance and might substantially improve future therapeutic strategies.
Ipsita BanerjeeUniversity of Pittsburgh
Project Title: Defining Mechanisms Controlling Stem Cell Fate During Differentiation
Grant ID: DP2-OD-006491
Regenerative medicine largely relies on cell-based therapy for treatment of degenerative diseases such as diabetes, heart failure, and Parkinson’s disease. Embryonic stem cells and recently established induced pluripotent stem cells will be able to contribute significantly in generating a renewable source of transplantable, fully functional cells. In spite of diverse efforts in deriving mature cellular phenotypes from these pluripotent cell types, what is lacking is a thorough understanding of the mechanism governing differentiation and lineage commitment of these pluripotent cells, hence resulting in incremental advancement of the field. My objective is to address the complex differentiation process from a completely different approach, which will have the potential to shift paradigms in regenerative medicine and stem cell bioengineering as a whole. The objective of the proposed research is to develop an insightful mechanistic understanding of the process of differentiation through an integrated experimental and theoretical approach organized around three basic questions: 1) How do the transcription factors interact in controlling and deciding on a cell lineage? 2) How do environmental perturbations influence these networks toward desired lineage? 3) How do gene and protein networks operating at the cellular level govern the tissue functionality at the systems level? These questions will be addressed in a system of embryonic stem cells differentiating to pancreatic islets, using a bottom-up approach where molecular-level information will be integrated to predict tissue-level functionality. Successful completion of this project will directly impact cellular therapy-based regenerative medicine and will pave the way for mechanistic understanding of disease progression and potential therapeutic intervention.
Edward B. Brown, IIIUniversity of Rochester Medical Center
Project Title: Exploiting Collagen Organization to Predict and Prevent Tumor Metastasis
Grant ID: DP2-OD-006501
The extent and nature of the ordering of collagen fibers within a tumor has significant influence on metastasis: In murine breast tumor models, tumor cells move toward blood vessels along fibers that are visible via second harmonic generation (SHG), and SHG is exquisitely sensitive to molecular ordering. Tumor cells that move along SHG fibers are significantly faster than those moving independently, and SHG-associated motility is correlated with metastatic ability. Furthermore, the tumor-host interface contains radially oriented SHG fibers associated with tumor cells invading the surrounding tissue. Lastly, we have shown that treatment of tumors with relaxin, known to alter metastatic ability, alters collagen ordering as detectable by SHG. Consequently, we believe that the process of establishing ordered fibers offers an exciting, and currently unexploited, therapeutic target. To take advantage of this, we must first learn the cellular players and molecular signals by which collagen ordering is induced. Therefore, in this application we propose to determine the key cells and signals which influence the ordering of collagen in breast tumors. The tumor-draining lymph node is the first bridgehead for many metastasizing tumor cells, and we have exciting preliminary data suggesting that changes in collagen ordering within the node are evident (via SHG) before clinical detection of metastatic cancer, therefore we will also determine the key cells and signals which influence the ordering of collagen in the draining lymph node. Additionally, we will determine if SHG measures of collagen ordering in breast tumors and draining nodes are clinically useful predictors of metastatic outcome in breast cancer patient biopsies. This project has a high impact because it has two independent pathways to clinical relevance, by developing promising antimetastatic drug targets, and by developing an optical method to predict metastatic ability.
Fernando CamargoChildren’s Hospital Boston
Project Title: Analysis of Stem Cell Dynamics and Differentiation by Cellular Barcoding
Grant ID: DP2-OD-006472
The changing demographics of developed nations underscore the need for regenerative medicine approaches to combat the clinical and financial burden of degenerative diseases. The basic understanding of how tissues are normally maintained by their resident stem cells is, therefore, key for pursuing regenerative approaches. Though a great deal of knowledge has been gained through the use of traditional experimental approaches over the past two decades, limitations and drawbacks of these techniques have precluded us from gaining a complete understanding of stem cell function, particularly in the in vivo setting. The goal of my New Innovator proposal is to develop a novel experimental paradigm for the study of stem cell biology. In this model, individual stem cells in a population are uniquely and genetically tagged in situ and these unique genetic tags, or barcodes, can then be used to dynamically monitor individual stem cell activity, lifespan, and differentiation in highly complex populations over time. We believe that this model can give us an unprecedented, high-resolution picture of the inner workings of a complex and dynamic stem cell system, and allow us to answer long-standing biological questions. Our findings ultimately may uncover conserved mechanisms of stem cell maintenance that are perturbed in old age or other disease contexts. Though this proposal will address the biology of the normal and malignant hematopoietic (blood-forming) stem cell compartments, the modular nature of our model makes easily adaptable to any tissue. Our model is also suitable, among other things, for the study of aging and immunological problems.
Nikos ChronisUniversity of Michigan
Project Title: A Biochip for Point-of-Care HIV/AIDS Diagnosis in the Developing World
Grant ID: DP2-OD-006458
HIV/AIDS is one of the most destructive pandemics in human history, responsible for more than 25 million deaths. More than 30 million people live with limited or no access to therapeutic treatments, mainly due to the high cost of highly active antiretroviral therapies (HAART) and current diagnostic tests as well as due to the lack of basic infrastructure (e.g., lack of electricity, no trained personnel) that can support these tests. The need for innovative, inexpensive diagnostic instrumentation technology that can be used in resource-limited settings is immediate. While programs that offer free HAART are being implemented in resource-limited settings, no diagnostic tests are available for evaluating the efficacy of HAART provided for the reasons mentioned above. Efficient management of HAART requires monitoring the course of HIV infection over time. The World Health Organization recommends the CD4+ T-cell count test for monitoring the clinical status of HIV individuals in resource-limited settings. We propose to develop a portable, inexpensive, MEMS (MicroElectroMechanical Systems)-based, imaging system for counting the absolute number of CD4 cells from 1 µl of whole blood. We use the term “imaging system” to denote the different approach we follow for counting CD4 cells: Rather than reading single cells one by one (as is done with flow cytometry), our system can image simultaneously thousands of individual cells, pre-assembled on the surface of a biochip. Although the proposed imaging system can replace current expensive cell-counting instrumentation, our goal is to develop a system that can reach the end-user wherever limited infrastructure is present and no access to a hospital or clinic is possible. Such technology will not only make it possible to monitor the efficacy of an individual’s HAART in the developing world, but it will make more medicines available by identifying patients who need a treatment from patients who do not need it.
Ted CohenBrigham and Women's Hospital
Project Title: Prevalence, Risk Factors and Consequences of Complex M. tuberculosis Infections
Grant ID: DP2-OD-006663
Tuberculosis (TB) is an infectious disease of global importance; in 2006, there were more than 9 million incident cases and 1.7 million deaths attributable to TB. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB and the convergence of the HIV and TB epidemics are threats to effective TB control. Furthermore, evidence exists that previous M. tuberculosis infection confers limited immunity to re-infection, that an individual can simultaneously harbor more than one distinct strain of M. tuberculosis, that distinct lineages of M. tuberculosis differ in their virulence characteristics, and that M. tuberculosis diversifies within a host. Each of these factors contributes to the within-host complexity of M. tuberculosis infection and presents complications for the treatment of individuals and the control of disease in populations. I propose an observational study among individuals starting treatment for TB in Lima, Peru, and Pietermaritzburg, South Africa, to evaluate the prevalence, risk factors, and consequences of complex M. tuberculosis infection. I will: 1) estimate the site-specific prevalence of multiple-strain M. tuberculosis infection and clonal heterogeneity among individuals at the time of initial diagnosis, 2) determine the host- and strain-related risk factors for multiple-strain infection and clonal heterogeneity, 3) evaluate the effect of multiple-strain infection and clonal heterogeneity on early response to standard first-line treatment regimens, and 4) develop mathematical models to examine the individual- and population-level effects of multiple-strain infection and clonal heterogeneity.
Kathy DeRiemerUniversity of California, Davis, School of Medicine
Project Title: Transmission and Virulence of Mycobacterium tuberculosis
Grant ID: DP2-OD-006452
Why do some individuals who are exposed to Mycobacterium tuberculosis become infected, while others do not? Of those who are exposed and infected, why do some individuals rapidly progress to active disease, while others remain asymptomatic, latently infected, or progress to active disease decades later or not at all? The observed heterogeneity in individuals' responses to exposure and infection might be explained by differences in the transmission characteristics of M. tuberculosis and its virulence in the human host. Our goals are to: 1) identify the gene expression profiles of M. tuberculosis in sputa from patients with latent TB infection and active disease; 2) identify sets of genes that characterize the early infection, pro-inflammatory immune response post-infection, and active disease stages of M. tuberculosis in the human host; and 3) identify differential gene expression patterns attributable to different strains, including drug-resistant and pan-susceptible strains of M. tuberculosis. We propose a case-control study of tuberculosis patients, their infected and uninfected contacts, and neighborhood healthy controls. From enrolled study participants, we will obtain information, a cough sample with sputa, and a blood sample. The sets of gene expression patterns—diagnostic signatures—could be translated into new, accurate, and rapid diagnostic tests. We will recruit and enroll patients in Shanghai, China, a city with over 6,000 new TB cases annually and the point of departure for many migrants to the United States. Our discoveries will have a significant impact on the tuberculosis epidemic worldwide, a global health emergency that caused 9.2 million new cases and killed 1.7 million persons in 2006. We seek strategies to target scarce public health resources to prevent new cases of active tuberculosis in the United States and globally.
Elva D. DiazUniversity of California, Davis
Project Title: Generation of Tumor Stem Cell Lines for Directed Therapeutics of Brain Cancer
Grant ID: DP2-OD-006479
Tumors of the central nervous system (CNS) represent nearly one quarter of all childhood cancers. Although progress has been made in the treatment of some types of childhood cancer, the outcome for children with primary CNS tumors has remained bleak and little advancement has been made in the last decade. In addition, due to the adverse effects of the tumor on brain development or the treatment required to control its growth, survivors of childhood brain tumors often have severe neurodevelopmental defects that negatively impact their quality of life. Thus, there is a need for better treatments specific for childhood brain tumors. Current models suggest that only a few atypical cells within the cancerous mass are responsible for the initiation, growth, and recurrence of brain tumors. These transformed cells have both the defining properties of neural stem cells and the ability to initiate cancer, thus these cells are referred to as “brain tumor stem (BTS) cells.” While the isolation of neural stem cells is fairly well established, the isolation of BTS cells remains a difficult and complex issue, suggesting the need for innovative approaches to isolate and characterize these cells. The development of induced pluripotent stem cells (somatic cells that have been reprogrammed to an embryonic-like pluripotent state by retroviral-mediated introduction of specific transcription factors) represents a powerful new approach that might alleviate such confounding issues. Thus, the goals of the proposed project are: 1) to reprogram brain tumor cells toward a more stem-like phenotype, 2) to characterize the tumorigenic potential of such reprogrammed tumor stem-like cell lines, and 3) to identify chemical compounds that specifically target the reprogrammed tumor stem-like cells. Completion of these studies will provide a directed strategy for novel therapeutics to specifically target the cellular population responsible for the initiation, growth, and recurrence of pediatric brain tumors.
Adam J. EnglerUniversity of California, San Diego
Project Title: “Smart” Materials to Engineer a More Complete Stem Cell Niche
Grant ID: DP2-OD-006460
One of the recent paradigm shifts in stem cell biology and regenerative medicine has been the discovery that stem cells can begin to differentiate into adult tissue cells when exposed to intrinsic properties of the extracellular matrix (ECM), such as matrix structure, elasticity, and composition. ECM regulation of stem cells has also been shown to be as sensitive as well-studied soluble growth factors, and together in the body, they comprise the stem cell niche, or “microenvironment.” However, these cues have typically been studied as isolated stimuli where no single cue, whether a growth factor or an ECM property, has been sufficient to generate the appropriate type of differentiated cells for a given regenerative cell therapy. Moreover, as stem cells mature in the body during development, their microenvironment is highly spatially and temporally controlled, yet our ability to dynamically regulate the niche as the body does has not been developed and is probably a critical requirement for developing differentiated cells from stem cells. Therefore, I propose to substantially advance the field of stem cell biology by developing a new hybrid hydrogel system using a unique combination of conventional polymer chemistries. These gels, comprised of hyaluronic acid-co-acrylamide polymer, should present spatially and temporally controlled matrix properties that mimic their presentation during development. When combined with spatially patterned growth factors, these cues could more accurately recapitulate the development of a specific tissue ex vivo, which may improve the differentiated cell sources used for cell-based therapeutic applications.
Alla GrishokColumbia University College of Physicians and Surgeons
Project Title: Investigating the Potential of Endogenous RNAi in Mediating Adaptation to Environment
Grant ID: DP2-OD-006412
RNA interference (RNAi) provides defense against exogenous nucleic acids, such as viruses and transposons, in diverse organisms. The production of short interfering RNAs (siRNAs) antisense to the viral or transposon sequences is a hallmark of the RNAi response. The discovery of the endogenous antisense siRNAs (endo-siRNAs) matching thousands of protein-coding sequences in C. elegans and identification of similar molecules in Drosophila and mammals poses a question about their function. Our recent microarray analysis of genes misregulated in the RNAi pathway mutants in C. elegans revealed preferential targeting by the RNAi components and endogenous short RNAs of genes whose inactivation is beneficial for stress resistance and lifespan extension, such as genes encoding translation factors. We propose that pools of endogenous short RNAs in C. elegans are subject to natural selection. Therefore, the composition of siRNAs in populations is adjusted in response to the environmental changes to achieve maximum fitness. The goal of this project is to test the above model. We will select populations of C. elegans resistant to specific environmental conditions and test these populations for the accumulation of endo-siRNAs antisense to very specific genes whose inactivation allows survival under the tested condition. We already established a correlation between thermotolerance and accumulation of endo-siRNAs specific to translation initiation factors. In addition, natural selection for survival on the nematocidal drugs ivermectin and levamisole will be used to generate C. elegans strains resistant to drugs due to epigenetic endo-siRNA-based inactivation of specific genes. Proving the existence of a siRNA-based epigenetic natural selection would represent a fundamental breakthrough in basic science. Epigenetic RNAi-based mechanisms are not likely to be limited to lower organisms and may be involved in the immune escape and drug resistance of malignant tumors and in other cases when cells evolve to escape the action of therapeutic agents.
Ira M. HallUniversity of Virginia
Project Title: Extent, Origin, and Control of Structural Variation in Mammalian Genomes
Grant ID: DP2-OD-006493
Mammalian genomes have a complex physical structure shaped by myriad duplications, deletions, and rearrangements, and this structure varies considerably among the populations and individuals of a species. These "structural variations" are of special importance to our understanding of evolution and disease because single mutational events can affect large phenotypic changes and because mutation rates vary dramatically among different genomic loci. We are only in the very early stages of understanding how structurally plastic genomes truly are and why they are this way. Massively parallel paired-end DNA sequencing now offers the opportunity, in theory, to reconstruct the architecture of entire genomes on a routine basis. However, the practical utility of these methods remains limited by the significant computational challenges posed by proper data interpretation and by cost. Over the past year, we have developed novel experimental and computational tools, and we are now close to our initial goal of being able to comprehensively map structural variation in mammalian genomes, at reasonable cost, and with modest computing power. We propose to apply these tools to examine structural variation in three especially revealing contexts: among diverse mouse strains with shared genealogical origins, among related mouse colonies separated by ~2,000 generations of breeding, and among single cells from diverse somatic lineages of the body and brain. In each case we will systematically identify and characterize "hotspot" loci that mutate at elevated rates. These studies will yield an unbiased evaluation of the extent and origin of structural variation in mammalian genomes and will enable us pursue our final goal: to develop a high-throughput platform for identifying factors that affect structural mutation rates. This work has immediate relevance to medicine, considering that structural genomic variation has emerged as a major cause of both inherited and spontaneous human disease.
Sarah HeilshornStanford University
Project Title: Engineering 3D In Vitro Niches to Reveal Fundamentals of Cellular Biomechanics
Grant ID: DP2-OD-006477
The development of tissue culture techniques by Ross Granville Harrison in 1907 has been cited as one of the ten greatest discoveries in medicine and enabled monumental advances in biological understanding. Despite the enduring importance of in vitro culture in modern biomedicine, the technology of mammalian cell culture has remained largely unchanged since the 1940s: Cells are cultured on hard, flat substrates and surrounded by homogeneous solutions of medium that do little to recreate the exquisite microenvironments found in vivo. Cells are well known to respond to multiple cues found within their in vivo niches, e.g., concentration gradients of soluble and tethered biochemicals, matrix rigidity, patterns of matrix ligands, and interactions with other cell types; however, few methods exist to recapitulate these cues in in vitro cell culture studies. To address these limitations, I propose creating versatile, three-dimensional in vitro niches with precise spatial and temporal resolution of cellular cues. These three-dimensional microenvironments will be fabricated using innovative and transdisciplinary approaches that combine advances in protein engineering, biomaterials, and microfluidics with traditional cell biology protocols. As a model system, these in vitro niches will be used to quantitatively study the cellular biomechanics and signaling mechanisms regulating neural progenitor cell (NPC) migration. NPC chemotaxis within gradients of soluble factors is hypothesized to be contextual and reliant on additional biomechanical cues from the 3D matrix. The presence of NPCs within specific niches of the brain opens up the tantalizing possibility that the adult central nervous system may be able to regenerate following injury or disease if NPCs were induced to migrate to sites of need. The development of quantitative, in vitro mimics of in vivo niches will have a profound impact on biomedical research by enabling scientists to test entirely new hypotheses about the interactions between different cells and their three-dimensional microenvironments.
K.C. HuangStanford University
Project Title: Engineering of Cell Shape and Intracellular Organization
Grant ID: DP2-OD-006466
A bacterial cell is much more than the sum of its parts. Most cellular functions are critically impacted not only by regulation of the genome and proteome, but also by the shape of the cell and how the shape dictates the localization of intracellular components. The ability to systematically manipulate cell shape will ultimately provide a powerful suite of applications in antibiotic drug development, synthetic biology, and biosensing. My laboratory will leverage insight from evolutionary, synthetic, and cell biological approaches to inform our ongoing development of quantitative, biophysical models of bacterial cell shape determination and growth. We have already successfully used modeling to predict the cell shape response to antibiotic treatment. We will focus our efforts on exploiting other predictions generated from quantitative models to re-engineer cell shape and redesign the intracellular localization landscape. For the period of this award, three design targets will be pursued that leverage our expertise in biophysical modeling of cell shape to probe key features of cell growth: 1) We will explore the evolutionary origins of cell shape determination by transplanting foreign cytoskeletal elements between closely related bacteria. 2) We will program specific intracellular organizational phenotypes to dynamically reengineer cell shape. 3) We will determine the tension sensitivity of the growth machinery to elucidate potential feedback mechanisms for cell shape maintenance. These targets will strategically expand the experimental focus of my laboratory. Success will address many longstanding questions of how cells determine their shape and how they utilize shape to regulate complex intracellular processes such as cell division. The physical principles of organization are likely to appear in diverse biological contexts, in both bacterial cells and in higher organisms. Ultimately, we will challenge our understanding of cell shape determination by transforming shape into an experimentally tunable parameter.
Sanjay K. JainJohns Hopkins University School of Medicine
Project Title: Novel Imaging Biomarkers to Address Fundamental Controversies in TB Pathogenesis
Grant ID: DP2-OD-006492
Recognizing that tuberculosis (TB) is still one of the leading causes of human death, the international health community has set ambitious targets to control TB by 2050. Unfortunately, this target cannot be achieved with current tools and requires the development and use of better anti-TB drugs/vaccines. Since Mycobacterium tuberculosis adapts to a quiescent physiological state—“dormancy”—and successfully evades anti-TB drugs and host immune responses for decades, understanding the kinetics of adaptive bacterial responses and the host-microenvironment is essential for developing better anti-TB drugs/vaccines. However, current tools for assessing bacterial-host kinetics in animal models are limited to analyzing postmortem tissues. Artifacts introduced during sacrifice/processing make them less reliable. Moreover, lesion-specific characteristics are generally not assessed separate from the whole organ. Since a different animal is sacrificed at every time point, bacterial-lesion kinetics in an individual animal can also never be assessed. We have pioneered the development of imaging biomarkers to assess M. tuberculosis bacterial burden in animal models. In this proposal, we will develop novel imaging biomarkers that will not only permit assessment of M. tuberculosis burden but also allow monitoring and localization of both adaptive bacterial responses and the host microenvironment (inflammation, hypoxia, and early immunity), in the same, live animal, over several time points. These tools will be utilized to address fundamental controversies in TB pathogenesis that cannot be tackled using current tools: 1) Are host tissue inflammation and hypoxia a sanctuary for “dormant” M. tuberculosis? 2) Where does “dormant” M. tuberculosis reside? 3) Is innate immunity required for controlling initial M. tuberculosis infection? Knowledge gained from this proposal will provide unique insights for developing better anti-TB drugs/vaccines. By permitting cost-effective, cross-species preclinical assessment, these tools will also dramatically reduce the time required for “bench-to-bedside” translation. Finally, since these tools are easily translatable, preclinical validation will lay the groundwork for their future use in humans.
Kevin A. JanesUniversity of Virginia
Project Title: Stochastic Control of Abnormal Morphogenesis Induced by the ErbB2 Oncoprotein
Grant ID: DP2-OD-006464
Cancer is a stochastic disease whose biology has been studied almost exclusively with deterministic approaches. Why? In this application, I propose to exploit the apparent randomness of cellular transformation to uncover new mechanisms involved in tumorigenesis. My focus is the ligandless receptor tyrosine kinase, ErbB2, which is overexpressed in 20–30% of breast cancers and is the target of anticancer drugs such as Herceptin® and Tykerb®. In a 3D in vitro culture model of mammary-acinar morphogenesis, inducible activation of ErbB2 causes hyperproliferative multiacinar structures that in many ways are reminiscent of early-stage breast tumors. Importantly, the penetrance of the phenotype is incomplete—only a random fraction of the cultured acini exhibit the morphogenetic defect when ErbB2 is activated. How this fraction is specified and the mechanism by which a multiacinus initiates are unknown. My hypothesis is that acute differences (dichotomies) in gene expression develop among acini and give rise to the distinct 3D phenotypes induced by ErbB2. The transcriptional dichotomies that exist before the appearance of the multiacinar phenotype will be the ones most likely to control it. However, without seeing the phenotype, it is impossible to know which ErbB2 structures will go on to develop abnormally. To overcome this challenge, we will use a new technique, called “stochastic profiling,” that I developed for discovering transcriptional dichotomies in a seemingly uniform cell population. We will apply stochastic profiling to a series of conditional ErbB2 homo- and heterodimer pairs that have different penetrances for the multiacinar phenotype. By mapping the transcriptional dichotomies to the differences in penetrance among dimer pairs, we will link upstream acinus-specific expression programs to downstream morphogenetic heterogeneities. The results from this project could explain mechanistically why only a fraction of ErbB2-overexpressing breast cancers respond positively to ErbB2-targeted therapeutics.
Melissa Lambeth KempGeorgia Institute of Technology
Project Title: Redox Regulation of Cellular Information Processing
Grant ID: DP2-OD-006483
Elevated concentrations of extracellular reactive oxygen species (ROS) are hallmarks of inflammation, and decades of medical research have focused on suppression of these molecules to treat pathologies as diverse as rheumatoid arthritis, cancer, and atherosclerosis with mixed results. More recently, researchers have discovered that these same molecules are produced during the course of normal signal transduction. In order to effectively treat inflammation, we must understand these distinct roles for reactive oxygen species. I propose an innovative research program that will elucidate the role of hydrogen peroxide, a key ROS, in normal cell signaling through computational models and laboratory experiments. This research will lead to a new, quantitative understanding of ROS and facilitate the development of effective antioxidant treatments for inflammation. This project will use three complementary approaches to evaluate the complex regulatory role of hydrogen peroxide on receptor-induced signaling. First, we will develop computational network models describing redox regulation of proteins in a time-dependent manner. Secondly, we are designing new methods to detect oxidative changes on multiple proteins simultaneously. These assays will allow investigation of the relationships between phosphorylation of signal transduction molecules and reversible thiol modifications. Finally, we have created a series of cell lines in which key components of the redox network have been perturbed that demonstrate augmentation and attenuation of receptor signaling. These lines will be used to systematically investigate the efficiency of three receptor networks–a pro-inflammatory cue (TNF-α), anti-inflammatory cue (TGF-β), and antigenic response (TCR)–under different oxidative environments. The results of these studies will provide the first computational modeling platform capable of interpreting incongruous literature reports of oxidative effects on cellular information processing. This project leverages my unique experience at the interface of immunology, systems biology, and metabolism to address a fundamental mechanism of cellular regulation critical for a large class of therapeutic drugs.
Gabriel KreimanChildren’s Hospital Boston
Project Title: Towards the Neuronal Correlates of Visual Awareness
Grant ID: DP2-OD-006461
The brain, a physical system composed of neurons and synapses, can give rise to what seems to be the least physical property of all: consciousness. How this transformation takes place has preoccupied generations of clinicians and scientists. Advances in neuroscience over the last several decades make it possible to enquire into the neural circuits responsible for consciousness. This proposal focuses on one particular aspect of conscious experience: the neuronal mechanisms and circuits that underlie visual awareness. We propose to study visual awareness using a combination of neurophysiology, psychophysics, and electrical stimulation. We take advantage of a rare opportunity to examine activity in the human occipital and temporal lobes using neurophysiology at high spatial and temporal resolution (neurons and milliseconds) while subjects report their perceptions. We propose two experiments where visual perception is dissociated from the visual input: binocular rivalry and motion-induced blindness. In both cases, perception changes in spite of a constant visual input. We investigate where, when, and how neuronal responses along the ventral visual cortex (from primary visual cortex to inferior temporal cortex) change their activity patterns with the perceptual alterations. Furthermore, we ask whether those neurophysiological responses are sufficient to elicit perception by electrically stimulating local circuits. Impairments in conscious processing can be devastating and are at the core of such seemingly diverse conditions as epilepsy, vegetative coma, schizophrenia, and autism. Furthering our understanding of the link between brains and minds in the context of vision will pave the way for addressing other aspects of consciousness and may have profound implications in changing how we think about and address these challenging disorders.
Christopher KristichMedical College of Wisconsin
Project Title: Genetic Approaches to Protein-Protein Interactions Mediating Antibiotic Resistance
Grant ID: DP2-OD-006447
Antibiotic-resistant bacteria, such as vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA), are major causes of hospital-acquired infections and are driving forces of an escalating health crisis. We will help address the burgeoning antibiotic resistance problem by leveraging the power of bacterial genetics via unbiased genetic selections to: 1) comprehensively identify protein-protein interactions in cellular pathways that result in antibiotic resistance, and 2) discover small molecules that disable these protein-protein interactions. The proposed research will jointly exploit our expertise in the development of genetic strategies and our ongoing interest in elucidating the fundamental mechanisms of bacterial antibiotic resistance. By focusing on protein-protein interactions, this research promises to: 1) reveal new insights into the underlying biology of antibiotic resistance mechanisms and their integration into the physiological processes of the bacterial host, 2) define new targets (in the form of protein-protein interactions) for innovative therapeutics to treat infections caused by drug-resistant pathogens, and 3) identify novel small-molecule drug candidates with unique modes of action. Our experimental design possesses critical strategic advantages. For example, our analyses will be done within the native context of the drug-resistant bacterial host (e.g., not by in vitro screens on isolated proteins), which will enable us to capture any potential, but as yet unknown, effects of dynamic cellular processes or post-translational modifications on key protein-protein interactions. Furthermore, we will employ powerful genetic selections capable of rapidly sifting through immense libraries to reveal even rare hits that, by definition, are functional in a physiological context. Collectively, these strategies will enable the discovery of unknown, unpredictable, and novel biological insights, not accessible by conventional means, that will be exploited to discover new candidate therapeutics with efficacy against drug-resistant bacterial infections.
Siavash K. KurdistaniUniversity of California, Los Angeles, David Geffen School of Medicine
Project Title: A Blueprint for Oncogenic Epigenetic Reprogramming
Grant ID: DP2-OD-006516
While cancer is a genetic disease, the cancerous cellular state is associated with multiple epigenetic alterations, including aberrant DNA methylation and histone modification patterns. A significant challenge in cancer biology is to elucidate the precise order of epigenetic alterations during tumor initiation and progression and their contributions to the transformed phenotype. To meet this challenge, one requires a model of cellular transformation that is temporally traceable from a normal to a malignant state. Cancer cell lines are not necessarily good models, as they have already accumulated hundreds to thousands of genetic and epigenetic alterations. Here, I propose to study the oncogenic transformation of normal human cells by viral oncoproteins as a model to determine the precise epigenetic reprogramming events occurring along the path of neoplastic transformation. Viral oncoproteins such as the adenovirus small e1a or papillomavirus E7 have been extraordinarily useful in delineating the central molecular players that regulate cell proliferation such as the retinoblastoma (RB) and p53 tumor suppressors. Our work has recently elucidated a defined global epigenetic reprogramming by one viral oncoprotein, e1a, that forces normal cells to escape quiescence—a hallmark of cancer. Importantly, e1a directly implements a precise and coordinated mechanism of regulation of thousands of host cell genes leading to cellular transformation by interacting and rearranging specific epigenetic modifiers across the whole genome in a time-dependent manner. This provides a powerful model that is amenable to time series measurements with phenotypically defined endpoints, enabling one to delineate the successive order of epigenetic alterations that contribute to oncogenic transformation. By understanding how e1a orchestrates a specific sequence of epigenetic alterations for cellular transformation, we should learn greatly about the functions and mechanisms of fundamental epigenetic processes in normal biology and human disease, especially cancer.
Naa Oyo A. KwateColumbia University Mailman School of Public Health
Project Title: Immunologic Effects and a Structural “Countermarketing” Intervention: Racism, the HPA Axis, and African American Health
Grant ID: DP2-OD-006513
The overall aims of this project are to explore the effects of multiple levels of racism on the immune function and overall health of urban African Americans and to test a novel structural-level intervention to reduce the negative impact of racism. Significant disparities in major chronic illnesses, including cardiovascular disease, cancer, and overweight/obesity, continue to describe the current picture of health for African Americans. Researchers have long understood stress to play a critical role in negative health outcomes, and particular attention has been paid to the hypothalamic-pituitary-adrenocortical (HPA) axis as a key pathway. Because experiences with racism constitute a significant stressor in the lives of African Americans, understanding the ways in which racism activates the axis will have profound meaning in addressing the determinants of African American health disparities. More broadly, given the role of the HPA axis in many systems, the proposed research has the potential to uncover critical information on the impact of social processes on overall physical and mental health and to delineate unstudied paths in brain-behavior relationships. In two sub-studies, the proposed research will enroll urban African Americans from New York City in longitudinal investigations. Study 1 is an investigation of how neighborhood-level institutional racism and perceived individual and collective racism affect immune and metabolic function and overall physical health, psychological wellbeing, and health behaviors. Study 2 is a neighborhood-level intervention to minimize the likelihood of internalized racism via a racism "countermarketing" campaign. Outdoor advertising will be employed to deliver stark facts about American inequality in predominantly African American neighborhoods, thereby raising consciousness and minimizing negative health outcomes. Taken together, the proposed research attempts to answer two critical unanswered questions in biomedical and behavioral research: 1) How does racism get into the body? and 2) What do we do about it?
KiBum LeeRutgers, The State University of New Jersey, New Brunswick
Project Title: Combinatorial Approaches for Studying Multiple Cues Regulating Human Pluripotent Stem Cell (hPSC) Fate
Grant ID: DP2-OD-006462
Human pluripotent stem cells (hPSCs) are promising resources as cell-based therapies for the debilitating injuries caused by many neurodegenerative diseases. However, controlling hPSC differentiation into lineage-specific neural cells is one of the most important problems needed to be addressed before their potential for neuroregenerative medicine can be fully realized. A detailed insight into the functions of extracellular microenvironments and intrinsic cellular regulators which dynamically regulate the hPSC neurogenesis into neural/neuronal cells is a prerequisite for addressing the aforementioned challenges. However, functions of hPSC microenvironments are much more complicated to investigate because of our lack of knowledge about the multiple signals inducing differentiation and limited methods available for investigation. Therefore, the primary focus of our study is to develop innovative methods to identify optimal cues for hPSC differentiation into subtype-specific neurons and genetic manipulation of hPSCs using nonviral, siRNA-based transfection tools. Our innovative approaches will allow for the establishment of novel cell-based assay tools and siRNA-based genetic manipulation tools for selective and efficient neurodifferentiation of hPSCs. Moreover, efforts will be made to integrate these studies into one multianalytic microfluidics platform for synchronized control of microenvironmental cues and intrinsic cellular regulators. The PI’s research experiences in nanoscale biomaterials, functional genomics, and stem cell biology and current interdisciplinary research programs aiming at investigating cellular interactions within microenvironments would be critical to develop the aforementioned innovative tools.
Daniel A. LimUniversity of California, San Francisco
Project Title: Chromatin-Based Cellular Memory in Neural Stem Cells
Grant ID: DP2-OD-006505
This proposal addresses two fundamental questions at the crossroads of epigenetics, stem cell biology, and regenerative medicine that relate to the chromatin-based cellular memory system. 1) Do chromatin modifications at specific genetic loci predict the progressive “restriction” of differentiation potential that occurs in neural stem cells during brain development and into adulthood? 2) Can cellular memory systems be partially “erased” or “reset” at the chromatin level in precursor cell populations to broaden their developmental potential? These studies should greatly advance our understanding of how precursor cells “remember” both their temporal and positional identities as well as determine whether this cellular memory system can be manipulated for novel therapeutic strategies. Three areas of impact are: developmental neurobiology, where results shed light on epigenetic mechanisms of neuronal and glial differentiation; regenerative medicine, where insight gained may suggest novel methods of cell fate specification; and cancer biology, where results may reveal how certain chromatin derangements can promote brain tumors. First, we propose investigating the changes in chromatin modifications that occur along a neural stem cell continuum from the embryo and into adulthood. Our proposed methods utilizing cells acutely isolated from the brain represent a significant advancement upon current cell culture-based studies. To accomplish this, we must innovate new, integrative approaches for chromatin study. We will also employ novel and as of yet unproven approaches to “reset” chromatin memory of cell identity with the purpose of altering cell fate. Given that these ideas concerning the chromatin basis of cellular memory and strategic epigenetic manipulation are new and relatively untested, the level of risk in our proposal is substantially higher than in traditional investigator grants. We wish to embark on this tangent from our current studies to broaden the impact of our research and explore fundamental principles of cellular memory in stem cell biology.
Stavros LomvardasUniversity of California, San Francisco
Project Title: Characterization of the Role of CpA Methylation in Neuronal Plasticity
Grant ID: DP2-OD-006667
Our brain displays an astonishing degree of plasticity. Experiences from a constantly changing environment generate, modify, and eliminate synapses and alter the function of our neurons. Extensive research over the last three decades has demonstrated that long-term potentiation is a process that requires enduring changes in gene expression. Although transcription factors mediate most of these changes, it is the covalent modifications on DNA and chromatin that render this changes long-lasting. Among these “so called” epigenetic changes, DNA methylation is the only one that cannot be enzymatically reversed. DNA methylation on CpG islands is a well established mechanism of gene silencing. Here, we show that we discovered a novel epigenetic modification, the methylation of CpA dinucleotides. Using a novel, genome-wide method to detect CpA methylation in primary neurons, we made the remarkable observation that CpA methylation appears only on actively transcribed genes. Moreover, our preliminary data suggest that this modification can be modulated by neuronal activity, exactly like the transcription status of the genes that it marks. An irreversible modification that can enhance or modulate gene expression could have profound consequences in neuronal plasticity. Therefore, we propose experiments that will dissect the role of CpA methylation in gene expression and neuronal function.
Andre G. MachadoCleveland Clinic Lerner College of Medicine-CWRU
Project Title: Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Modulation of the Affective Sphere of Chronic Neuropathic Pain
Grant ID: DP2-OD-006469
Chronic neuropathic pain is a common cause of disability in the population. Most treatment options for patients with medically refractory neuropathic pain, such as spinal cord stimulation, thalamic deep brain stimulation, or intrathecal infusion of narcotics, are aimed at producing analgesia and are known to have limited efficacy. We propose an innovative, neuromodulation-based approach to treat patients with central thalamic pain syndrome, a particularly severe form of neuropathic pain characterized by relentless anesthesia dolorosa resulting from injury to the thalamic sensory pathways. We depart from the traditional goal of intervening in the sensory discriminative neural pathways of pain transmission in order to produce analgesia. Instead, we plan to target with deep brain stimulation (DBS) the ventral area of the anterior limb of the internal capsule (ALIC), a region densely populated by fibers related to neural networks related to the control of behavior and emotion. By electrically stimulating these networks, we expect to modulate the affective sphere of patients with otherwise intractable pain and, consequently, reduce pain-related disability. We hypothesize that the improvement in pain-related disability associated with modulation of the affective pain sphere will not be dependent on analgesic effects. For this reason, the visual analog scale will be used as a secondary outcome measure to control for pain levels and analgesia, but the primary outcome measure of the study will be the pain disability index. Patients enrolled in this research will undergo baseline and post-DBS double-blinded evaluations for a period of six months, followed by chronic open-label stimulation. The neural circuits of emotion control and the effects of DBS upon these networks will be studied at regular intervals with functional magnetic resonance imaging and magnetoencephalography.
David MasopustUniversity of Minnesota Medical School
Project Title: Maximizing CD8 T Cells for Protection
Grant ID: DP2-OD-006467
HIV has claimed >25 million lives. Two decades of research, but no vaccine. Theoretically, generation of CD8 T cell immunity may succeed where traditional, neutralizing antibody-dependent vaccines have failed. But nascent efforts have consistently failed to prevent chronic SIV infection in monkeys following a stringent challenge, and the first human HIV CD8 T cell vaccine trial was a complete failure. Why? Is a preventative CD8 T cell vaccine impossible, as many now suggest? We hypothesize that past efforts have been crippled by a safety-first approach and relative ignorance of the importance of memory CD8 T cell quantity, quality, and location to protection. Current approaches are largely refinements of past failures. A bolder approach is long overdue, at least in animal models where safety requirements are less stringent. What could SIV-specific memory CD8 T cells accomplish if they were 500-fold more plentiful than what is established by current vaccination strategies? What if these cells were preferentially located at common portals of viral entry and destroyed infected host tissue quickly upon contact? If a vaccine converted most CD8 T cells into HIV- or SIV-specific memory cells, could they fully protect the host and eliminate the infection completely? Or are CD8 T cells incapable of fulfilling this goal, even under ideal scenarios? This proposal will answer these essential questions. Moreover, it will test the limits of memory CD8 T cell generation and define CD8 T cell correlates of protection. If successful, this study may demonstrate that a preventative HIV vaccine is theoretically possible.
J. Rodrigo MoraMassachusetts General Hospital / Harvard Medical School
Project Title: Reassessing the Physiological Role of Gut-Specific Lymphocyte Homing: Implications for Autoimmunity and Tolerance
Grant ID: DP2-OD-006512
Oral immunological tolerance is an essential although poorly understood phenomenon by which the immune system becomes “nonresponsive” against antigens administered via the intestinal mucosa. Although this process is vital for the co-existence with nonpathogenic intestinal antigens, such as food and normal microbial flora, the mechanisms responsible for oral tolerance remain poorly understood. Lymphocyte migration (homing) is essential for protective and pathological immune responses, and we and others have demonstrated that gut-associated, antigen-presenting dendritic cells instruct lymphocytes to express gut-specific homing receptors, integrin α4β7, and chemokine receptor CCR9, by a mechanism dependent on the vitamin A metabolite retinoic acid (RA). Importantly, RA also contributes to the generation of regulatory T lymphocytes (TREG), which have been shown to be important for the establishment of oral tolerance. Given that RA induces gut-homing lymphocytes and also promotes TREG differentiation, I hypothesize that RA is essential for the establishment of oral tolerance 1) by inducing gut-tropism and “sequestering” potentially pathogenic T lymphocytes in the intestinal mucosa, and 2) by promoting TREG differentiation in the gut. If successful, my work will highlight a new physiological role of gut homing in the establishment of oral tolerance, providing also a straightforward approach to induce immune tolerance using RA, which could be used in the treatment of autoimmune diseases.
Alysson R. MuotriUniversity of California, San Diego School of Medicine
Project Title: Modeling Autism with Human Pluripotent Cells
Grant ID: DP2-OD-006495
Autism and autism-spectrum disorders (ASD) are highly heritable, complex neurodevelopmental diseases where different gene combinations may play a role in different individuals. Nevertheless, the study of mutations in specific genes is helping to characterize the molecular mechanism responsible for subtle alterations in the nervous system, perhaps pointing to a general mechanism for the disorder. Here, we propose a novel approach to study ASD. Using Rett syndrome (RTT) as a pilot disease, we developed an in vitro system deriving induced pluripotent stem cells (iPSC) from RTT patients’ fibroblasts. RTT patients have several autistic features and are part of ASD. RTT patients have defined mutations in the X-linked gene encoding the methyl-CpG binding protein 2 (MeCP2). RTT patients’ reprogrammed cells can generate human neurons carrying different types of MeCP2 mutations. Deep sequencing will be used to analyze gene expression during the transition steps of differentiation, simulating early stages of human neural development. The system will allow us to study the relationship of gene expression of coding and non-coding RNAs to the cellular and network phenotypes, such as neuronal arborization, synapse formation, and network electrophysiology. Moreover, we will use a chimeric brain system to study the effects of environment in human RTT neurons. In a future step, we will repeat the strategy using different single-gene mutations that also lead to the autistic diagnosis. The data generated will help to reveal and understand possible common mechanisms present in ASD.
Sunitha NagrathMassachusetts General Hospital / Harvard Medical School
Project Title: Engineering Sensitive Microfluidic Multiplex Technology for Isolating Circulating Endothelial Progenitor and Tumor Cells to Study Angiogenesis and Metastasis in Cancer Development and Progression
Grant ID: DP2-OD-006672
Despite major strides in understanding of the molecular basis of cancer and cancer therapeutics, the complexities of the metastatic process remain poorly understood. Especially in colorectal cancer, understanding has been severely hampered by limited knowledge about the cells that cause the disease to metastasize through the bloodstream. Circulating cells of several lineages are thought to participate in angiogenesis, tumor growth, and metastasis. Among these, circulating tumor cells (CTCs) shed from the primary and metastatic carcinomas presumably give rise to bloodborne metastases, whereas circulating endothelial progenitor cells (CEPCs) from adult bone marrow initiate the premetastatic niche. This hypothesis gives rise to the “seed (CTCs) and soil (CEPCs)” concept. Although current models explain distinct and important aspects of metastasis, no single model can explain the sum of the cellular changes apparent in human cancer progression and metastasis. I will investigate the inextricable relationship between CTCs and CEPCs and their roles in carcinogenesis and metastasis. I propose to take a radical but integrated technology- and biology-based translational approach using microfluidic engineering tools to identify and study the biological relevance of these rare cells in peripheral blood. This approach will seek to answer the following questions: 1) Do the levels of CEPCs and CTCs in early and late stages of colon cancer correlate with each other along with tumor volume and clinical course? 2) Can dynamic changes in their load during the course of treatment plan predict the clinical outcome of the therapy? 3) Are there any changes to phenotypic and biological characteristics of these cells that distinguish prognostic subtypes? 4) What is the effect of CEPCs on CTCs when cocultured, and what is the fundamental biology of interaction? 5) Can we expand these cells in vitro to identify the true “metastatic precursors” or “cancer stem cells” and to determine biomarkers of angiogenesis and metastasis as potential therapeutic targets?
Vikas NandaRobert Wood Johnson Medical School/University of Medicine and Dentistry of New Jersey
Project Title: Computational Design of a Synthetic Extracellular Matrix
Grant ID: DP2-OD-006478
The extracellular matrix (ECM) is a complex network of collagens, laminins, fibronectins, and proteoglycans that provides a surface upon which cells can adhere, differentiate, and proliferate. Defects in the ECM are the underlying cause of a wide spectrum of diseases. The ECM mediates endothelial cell polarity and under normal conditions can suppress pre-oncogenic transitions to a neoplastic state. We are constructing artificial, de novo, collagen-based matrices using a hierarchic computational approach. These matrices will be physically characterized in the laboratory and used to probe the role of chemical and spatial organization in the ECM on the tumor-forming potential of adhered cells. We are using a two-stage, computational strategy to construct an artificial ECM. A key technology is protCAD (protein Computer Automated Design), a software platform developed in our laboratory specifically for computational protein design. In the first stage, the sequences of short collagen-like modules are designed to independently assemble into trimers of programmed stability and specificity. These modules are then covalently connected using flexible peptide linkers to facilitate the self-assembly of controlled, higher-order structures such as networks and fibrils. Encouraging experimental characterization of the first-generation collagen designs suggests that our computational strategy is likely to succeed. Synthetic ECMs will be useful in biomedical research and translational applications. Mammalian cells will be grown on anisotropic, self-assembling nanostructured matrices to assay effects on cell polarity, cytoskeletal orientation, and morphology. We will explore the ability of artificial matrices to suppress cell proliferation in the presence of various oncogenic signals. This will provide a powerful system for studying molecular aspects of the matrix biology of cancer. Successfully designed matrices will be applied to engineering safer artificial tissues.
Diane Joyce OrdwayColorado State University
Project Title: Immune Modulation by Highly Virulent Clinical Isolates of M. tuberculosis
Grant ID: DP2-OD-006450
The global epidemic of tuberculosis continues unabated. A particularly dangerous family of clinical strains is the "W-Beijing" family, many of which are highly drug-resistant (MDR). The substantial and relatively rapid transmission of these strains across the world has led people to believe that these particular isolates have some capacity or property to resist, and even subvert, the host immune response. Innovative work in the applicant's research group has uncovered the possibility that at least some of these isolates can induce Foxp3+ regulatory T cells that interfere with the proper expression of protective immunity in the mouse. Moreover, in the highly relevant guinea pig model, the applicant has published new flow cytometric technology to allow (for the very first time) the definition of the host pulmonary immune response. In this second model, many of these W-Beijing strains cause extremely severe lung pathology, far worse than that seen using "laboratory strains" of Mycobacterium tuberculosis. This is a very important point, because all new vaccine candidates to date have only been tested against these laboratory strains. In this proposal, we will use innovative new transgene mouse models to address the role of newly identified T cell subsets in modulating or subverting host immunity to this very serious group of pathogens, using our state-of-the-art Level III biosafety facilities. In addition, we will continue to develop innovative new methods to apply these studies to the (currently reagent-limited) guinea pig model. These studies will include three W-Beijing strains that cause a range (moderate to extremely severe) of lung pathology and several characterized examples of drug- sensitive/drug-resistant genetically matched pairs to test the concept that acquisition of drug resistance reduces bacterial fitness, and hence virulence.
Aydogan OzcanUniversity of California, Los Angeles
Project Title: Towards Mega-Throughput, Label-Free Genomics and Proteomics: Revolutionizing Microarray Technologies Using Lensless On-Chip Holographic Imaging and Nano-Plasmonics
Grant ID: DP2-OD-006427
Microarrays provide a high-throughput platform for various key studies in functional genomics, proteomics, epigenetics, medical diagnostics, and even tissue engineering. Together with advanced biochemical detection, imaging, and bioinformatics technologies, it is now possible to cost-effectively monitor the expression behavior of genes, proteins, or other biomarkers, as well as screening the genome and proteome content of various cell lines, on-chip drug profiling, or even detection of single-nucleotide-polymorphism. Therefore, microarray technologies provide a vital platform for performing high-throughput screening experiments that shed light on our understanding of cellular, genomic, and proteomic processes occurring at the nanoscale. In this proposal, we aim to create the next generation of microarray technologies to achieve an unprecedented mega-throughput, i.e., label-free imaging of millions of DNA/protein microspots would be feasible per second. We term the broad umbrella of these revolutionary technologies as Nano-plasmonic LUCAS. Specifically, we aim achieve a throughput of >120 cm2/second or >4.5 million spots/second for highly sensitive and label-free imaging of DNA/protein microarrays, which constitutes a speed improvement of >3 orders of magnitude when compared to the state of the art. Label-free imaging is especially important in not perturbing the natural biochemical, physical, and structural properties of the original molecule of interest. It also makes the measurements much more quantitative, significantly improving the data quality; eliminates inconvenient labeling steps which further reduces the cost; and avoids cross-reactivity issues among secondary probes, which can significantly improve the detection of weak or transitional molecular interactions. This mega-throughput capability will revolutionize the speed of progress that is taken in proteomics/genetics research by orders of magnitude that could eventually lead to the development of improved strategies/therapies for combating previously intractable biomedical problems and various diseases, including cancer. Furthermore, the Nano-plasmonic LUCAS platform does not require any lenses, microscope objectives, or other bulk optical components, and therefore offers an extremely compact on-chip platform that can easily be merged with microfluidic systems to permit point-of-care operation.
Christine K. PayneGeorgia Institute of Technology
Project Title: Intracellular Delivery and Targeting of Nanoparticles
Grant ID: DP2-OD-006470
Nanoparticles have important biomedical applications ranging from the treatment of human disease with gene therapy to understanding basic cellular functions with fluorescent probes. It is now possible to synthesize nanoparticles with nearly any property or size, direct them to specific cells, and functionalize them to target intracellular locations, but delivering nanoparticles across the plasma membrane to reach their targets remains a challenge. We have recently demonstrated the first method for noninvasive delivery of semiconductor nanoparticles, known as quantum dots (QDs), to the cytosol of multiple cells simultaneously. Delivery requires pyrenebutyrate in combination with a cationic peptide for direct interaction of the QD with the plasma membrane. The ability of QDs to cross the plasma membrane offers exciting possibilities for the delivery of other nanoparticles to living cells. The first goal of this research program is to determine the molecular and cellular mechanism of pyrenebutyrate-mediated delivery and extend it to other nanoparticles with the ultimate goal of targeting specific intracellular sites with nanoparticles of choice. Novel imaging methods, including single-particle tracking fluorescence microscopy, will be used to probe the motion of the nanoparticle and its interaction with pyrenebutyrate as it moves across the plasma membrane and through the cytosol. As pyrenebutyrate-mediated delivery may not be suitable for all nanoparticles and all applications, we will also work to develop a suite of cytosolic delivery and targeting methods that are based on the well-characterized endosomal uptake pathways. Both delivery methods will be carried out in conjunction with studies of cellular response to nanoparticles that aim to optimize delivery and minimize disruption. In the course of this research, QDs, which are sufficiently bright for imaging at the single-particle level, will be used to probe fundamental questions of cellular transport, including diffusion through the crowded cellular environment, vesicle-mediated transport, and nuclear targeting.
Anna A. PennStanford University School of Medicine
Project Title: Fetal Brain Damage: A Placental Disorder
Grant ID: DP2-OD-006457
The placenta has long been underappreciated and understudied by the scientific community. Improper function of this critical organ causes fetal abnormalities, premature labor, and the most common disease of pregnancy, preeclampsia. Despite the importance of the placenta, our understanding of its role in fetal development, especially at a molecular level, is crude. Sadly, our understanding of placental function may be compared to the knowledge of kidney function 50 years ago—we can describe the anatomy, but not the biology. My overarching goal is to use new molecular techniques to understand placental function and its relationship to fetal outcomes. Here my specific goal is to investigate how placental hormones shape fetal brain development. As an endocrine organ, the placenta produces a wide array of neuroactive hormones. This endocrine function can be disrupted in many ways—by abnormal gene expression, infection, prematurity—resulting in long-term damage. Preterm birth, affecting one-tenth of all deliveries, provides the most extreme case of hormone loss, but I hypothesize that it is just one of many cases in which placental dysfunction leads to brain damage. I will develop a series of animals in which individual hormones are specifically removed from the placenta at precise times during development. This system will allow the first direct, definitive tests of the placenta as a key regulator of fetal brain development. Both established hormones, such as progestins and oxytocin, and hormones that we have recently identified as neuromodulators made by the placenta, such as secretin, will be assessed. These experiments are likely to provide fundamental new insights in placental physiology and neurodevelopment, help redefine disorders such as cerebral palsy, autism and schizophrenia as disorders of the placenta, and open new avenues to therapeutic treatments to improve neurological outcome in fetuses and infants at high risk of developmental brain damage.
Patrick L. PurdonMassachusetts General Hospital / Harvard Medical School
Project Title: A Neural Systems Approach to Monitoring and Drug Delivery for General Anesthesia
Grant ID: DP2-OD-006454
General anesthesia is a drug-induced, reversible condition comprised of five behavioral states: loss of consciousness, amnesia, analgesia, lack of movement, and hemodynamic stability. Over 100,000 patients annually receive general anesthesia in the United States for surgical and medical procedures, yet the mechanisms for general anesthesia remain a mystery of modern medicine. While considerable safety improvements in anesthetic drugs and monitoring have been made over the past several decades, anesthesia-related morbidity remains a significant medical problem. Approximately 1 in 500 patients experience postoperative recall of events during surgery, which can result in post-traumatic stress disorder. Up to 41% of elderly patients suffer from postoperative cognitive dysfunction, with long-term deficits found in 13% of such patients. The human and economic costs of postoperative cognitive dysfunction will continue to grow significantly as the population of the United States ages and requires more frequent surgical and medical intervention. Other frequent side effects of general anesthesia include cardiovascular and respiratory depression, nausea, and vomiting. These instances of anesthesia-related morbidity occur because anesthetic drugs affect the entire central nervous system, not just the specific brain areas required to produce the state of general anesthesia. Because we are unable to monitor brain activity intraoperatively within the desired target brain systems, it is a challenge at present to balance the desired anesthetic state against unintended side effects. Furthermore, we lack the means to deliver anesthetic drugs specifically to anesthesia-related brain systems in order to avoid side effects mediated in other brain systems. We present here an innovative research program that will develop neural systems-based anesthetic monitoring and drug delivery to eliminate anesthesia-related morbidity. The proposed studies will result not only in dramatically improved anesthesia care in the long term, but will also result in fundamental discoveries and developments in systems neuroscience, neuroimaging, and drug delivery.
Shu-Bing QianCornell University
Project Title: Engineering Ubiquitin Ligases to Investigate Protein Aggregation and Neurodegeneration
Grant ID: DP2-OD-006449
Protein degradation lies at the heart of biological processes from signal transduction to cell cycle regulation. Compromised clearance of misfolded proteins from cells is the leading cause of human diseases such as neurodegenerative disorders. A common theme manifested in neurodegeneration is the accumulation of insoluble protein aggregates in the brain. However, the role of protein aggregation in the pathophysiology of neurodegeneration remains controversial. It remains a formidable task to remove protein aggregates from the affected neurons. In this proposal, we are taking a bold and innovative approach to attacking this exceedingly difficult problem: harnessing the ubiquitin/proteasome system to investigate protein aggregation and neurodegeneration. This proposal builds upon our previous development of methods to engineer single-chain ubiquitin ligase CHIP. We successfully established a novel strategy that enables us to alter the substrate binding specificity of CHIP without affecting its ligase activity. Using Huntington’s disease (HD) as a model, we propose herein to create recombinant ubiquitin ligases targeting the disease protein huntingtin (Htt) for ubiquitination. Our long-term goal is to define the structural features that determine the ligase activity of engineered ubiquitin ligases, elucidate the molecular mechanisms underlying protein aggregation and neurodegeneration, and evaluate the therapeutic potential of Htt-specific ubiquitin ligases. If successful, the engineered ubiquitin ligases will represent an unprecedented level of control over protein function in somatic cells, which would have direct impact on proteomic research by introducing novel “protein knockout” tools. In addition, the results of this project will provide unique insights into the fundamental cellular and molecular mechanisms underlying protein quality control and the pathophysiology of neurodegeneration. Application of these findings may help to delay or reverse the detrimental effects of neurodegeneration. Ultimately, it will serve as a prototype for the treatment of other neurodegenerative disorders, as well as non-neuronal human diseases.
Wei-Jun QianPacific Northwest National Laboratory
Project Title: A Universal Multiplex Assay System for High-Throughput Clinical Applications
Grant ID: DP2-OD-006668
Recent advances in genomics, proteomics, and metabolomics make the “omics” technologies powerful discovery-based tools for identifying candidate biomarkers for human diseases; however, it has not been successful so far to establish new biomarkers for clinical practice by utilizing these technologies. The main bottleneck lies in the lack of effective tools for high-throughput validation. To overcome this bottleneck I propose to develop a novel, “reagent-free,” mass spectrometry-based universal multiplex assay system that will provide high-throughput quantitative measurements for hundreds of low-abundance protein and metabolite analytes, independent of antibody-based reagents. The goal for this technology platform is to achieve a profound advance over current MS-platforms by providing >1000-fold enhancement in analyte signal intensities, sufficient for detecting low-abundance species, and >5000-fold improvement in resolving power for extremely high-specificity detection. These advances will be achieved by developing and integrating 1) a novel subambient pressure ionization source with nanoelectrospray array, 2) advanced ion-funnel interfaces, 3) novel multistage gas-phase ion mobility technology (differential mobility analyzer coupled to field asymmetric ion mobility spectrometry) for separating and selecting analytes of interest, and (4) a new triple-stage pentaquadrupole (QqQqQ) mass spectrometer for further isolating as well as detecting ions. The optimized platform will have a potential analytical throughput of >100 samples per day, sensitivity for broadly analyzing low-abundance candidate biomarkers without enrichment, and the multiplexing power to monitor up to 1000 analytes simultaneously. At least 3-4 orders of magnitude enhancement in sensitivity or detection dynamic range (i.e., to a level comparable or superior to current ELISA) is anticipated, a significant advance over current assay platforms. Such a novel assay system is a disruptive technology that will revolutionize many areas of biomedical research, current medical practice, and the future of health care, as well as the biomedical research field in general through instrument commercialization.
Leon ReijmersTufts University School of Medicine
Project Title: Molecular Analysis of Functional Neural Circuits
Grant ID: DP2-OD-006446
A functional neural circuit consists of a group of connected neurons that collaborate to execute a specific function of the brain. The understanding of the molecular mechanisms that underlie the development, maintenance, and experience-dependent modification of functional neural circuits is incomplete due to limitations of existing methods. I propose to generate a transgenic mouse that addresses these limitations by exploiting two recent methodological advances. The first advance is the TetTag mouse, which is a transgenic mouse that can be used to genetically tag a single functional neural circuit. This tag enables the selective molecular analysis of neurons that have a shared function. This method is more sensitive to changes within a single functional neural circuit than other available methods, which have to rely on spatial criteria and thereby include neurons that do not participate in the circuit of interest. The second advance is the Translating Ribosome Affinity Purification (TRAP) method, which enables purification of actively translated messenger RNA from a genetically defined group of neurons. TRAP analysis reflects changes at both the transcriptional and translational level, while other available methods only detect transcriptional changes. I will combine TetTag and TRAP within a single transgenic mouse to generate the first tool that enables the comprehensive analysis of all translational events within a single functional neural circuit. Neurons tagged with the TetTag mouse during fear conditioning provide a stable neural correlate of the fear memory. I will use the TetTag/TRAP mouse to purify actively translated messenger RNA from these tagged neurons in order to detect the protein synthesis events that underlie the storage of a memory. The TetTag/TRAP mouse can be used for the molecular analysis of various functional neural circuits, including those involved in memory, addiction, epilepsy, circadian rhythms, spinal cord regeneration, pain, brain development, and neuronal cell death.
Theresa M. ReinekeVirginia Tech
Project Title: Illuminating the Mechanistic Pathways of Polymer-Mediated Nucleic Acid Delivery
Grant ID: DP2-OD-006669
The wealth of information being obtained from genomic, proteomic, and glycomic research is allowing researchers to unravel the intricate genetic and epigenetic mechanisms associated with human health and disease. The intracellular delivery of nucleic acids to study these processes offers unprecedented promise for revolutionizing biomedical research and drug development. However, the nucleic acid delivery vehicle plays a central yet elusive role in dictating the efficacy, safety, mechanisms, and kinetics of gene regulation in a spatial and temporal manner, thus having a far-reaching impact in health-related research. To this end, we have developed several novel carbohydrate-containing polymers that have shown outstanding affinity to encapsulate polynucleotides into nanoparticles (polyplexes) and facilitate highly efficient intracellular delivery without toxicity. The goals of this project directly commence from our previous work where we aim to examine our wide-range of delivery vehicles for their mechanistic pathways and kinetics of nucleic acid encapsulation and intracellular transport from the cell surface to their final intracellular destination. We plan to examine 10 different carbohydrate-based polymers synthesized in our laboratory for their delivery mechanisms and kinetics with three polynucleotide forms: plasmid DNA, oligodeoxynucleotide decoys, and small interfering RNA, in two cell types, H9C2(2-1) and HeLa cells. The research program highlighted herein is driven by three specific goals: 1) to unravel the molecular-level interactions between structurally diverse yet analogous polymeric delivery vehicles and differing nucleic acid types and to correlate these interactions with the biological stability and mechanisms of the subsequent polyplexes, 2) to understand the interactions of these various polyplex types with cell surface glycosaminoglycans and compare polyplex structure to receptor selectivity and mechanisms of cellular uptake in two cell types, and 3) to decipher the intracellular trafficking pathways in a spatial and temporal manner from uptake to the final destination for each polyplex form with the two model cell types.
John L. RinnBeth Israel Deaconess Medical Center / Broad Institute of MIT and Harvard
Project Title: RNA and Chromatin Formation: From Discovery to Mechanism
Grant ID: DP2-OD-006670
A major outstanding challenge in biology is to understand how the exact same genomic sequence present in every cell takes on alternate epigenetic landscapes to confer a myriad of cellular functions, all while using ubiquitous cellular machinery. In addition to histone modifications and DNA methylation, RNA has been long thought to be involved in the establishment and inheritance of these epigenetic states, but is far less understood. Indeed, recently three examples of large noncoding RNAs (HOTAIR, XIST, and AIR) have been discovered that share a common theme: They physically associate with chromatin-remodeling complexes and are required to guide chromatin formation at specific genomic loci. Although these examples suggest a general mechanism, it is still unclear to what extent RNA plays a role in chromatin formation and the mechanisms by which this guidance occurs. Here we propose to comprehensively and systematically address the roles of large noncoding RNAs in the formation of chromatin structure. We will accomplish this by: 1) identifying and characterizing large noncoding RNAs that physically associate with chromatin remodeling complexes genome-wide across multiple yet related cell contexts, 2) defining the sites of regulation and the guidance mechanism to these genomic loci, and 3) identifying how these molecules and their mechanisms are misregulated in human disease. Together, our multifaceted experimental and computational approaches aim to “crack the code” of epigenetic establishment and maintenance. This will transform our understanding of genome regulation and establish a new paradigm for RNA in the guidance of chromatin formation.
Pardis Christine SabetiHarvard University
Project Title: Host and Pathogen Evolution in Lassa Fever
Grant ID: DP2-OD-006514
Disease-causing pathogens are among the most intriguing forces shaping human evolution, as they have a tremendous impact on our genome and themselves evolve over time. A genome-wide survey of human variation identified two genes biologically linked to Lassa fever as among the strongest signals of natural selection in West Africans. Lassa fever is a severe hemorrhagic disease endemic in West Africa, and our findings suggest it is an ancient selective force driving the emergence of genetic resistance. While poorly understood, Lassa fever has arguably the greatest potential impact of all infectious diseases of humans because of its unique status as both an immediate public health crisis and a category A potential bioterrorist agent. With the aim to pursue the intriguing signal of natural selection linked to Lassa fever, we first set out to address critical gaps in knowledge, capacity, and diagnostics. We established a basic diagnostic and research lab in Irrua, Nigeria, where yearly outbreaks of Lassa fever occur with population exposure of ~30%. Preliminary data suggests our initial measures have significantly reduced fatality from an estimated 65% to 20% among Lassa fever cases. We now aim to design a robust, field-deployable diagnostic, based on genome sequencing of diverse strains, to rapidly detect and distinguish Lassa virus strains. This work addresses immediate public health needs and sets the foundations for research into the genetic factors in both virus and human that underlie resistance to Lassa fever found among many West Africans. The ultimate goal of our work is to identify natural mechanisms of defense and illuminate the evolutionary adaptations that have allowed humans to withstand some of our most complex and challenging selective agents. Moreover, these efforts will create new opportunities in Lassa virus research, including investigations of viral pathogenicity and evolution and development of novel vaccines.
Magali Saint-GeniezSchepens Eye Research Institute / Harvard Medical School
Project Title: Bioengineering of Bruch's Membrane for the Treatment of Age-Related Macular Degeneration
Grant ID: DP2-OD-006649
Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries for those over 55. AMD is a complex and multifactorial disease described as two distinct types, dry and wet, leading to central vision loss. Dry AMD is characterized by the subretinal accumulation of deposits (drusen) and is associated with the progressive atrophy of the retinal pigment epithelium (RPE), choriocapillaris (vasculature supplying the photoreceptors), and retinal neurons. Dry AMD can progress to the proliferative form, wet AMD, where pathological and highly permeable vessels grow into the subretinal space. There is no treatment for dry AMD, and the current anti-angiogenic therapies for wet AMD, though effective at reducing vessel growth and permeability, do not address the underlying pathogenesis. Thus, the need for new therapeutic approaches is clear. Abnormalities in the RPE and the Bruch’s membrane (BrM), on which the RPE sit, are central to the development of AMD. Therefore, we are proposing a novel transplantation strategy to replace the degenerative RPE/BrM with the goal of preserving the choriocapillaris integrity and photoreceptor function. Previous attempts to transplant the RPE have failed largely because BrM alterations were not addressed. The aim of this proposal is to develop a co-culture system of RPE and endothelial cells on a biodegradable, biocompatible poly(ε-caprolactone) (PCL) polymer to bioengineer a RPE/Bruch’s membrane complex. The differentiation of the RPE and the formation of the BrM-like matrix on the PCL scaffold will be evaluated by immunohistochemistry, gene expression analysis, and electron microscopy techniques. Finally, the therapeutic potential of the RPE-PCL transplantation for patients with AMD will be determined in animal models of RPE damage. Results of these studies may permit the development of strategies aimed at replacing the diseased subretinal tissue with a bioengineered RPE/BrM prosthesis that could represent a therapeutic solution for all forms of AMD.
Wenying ShouFred Hutchinson Cancer Research Center
Project Title: Cellular Cooperation and Cheating: An Experimental and Mathematical Analysis
Grant ID: DP2-OD-006498
Cooperation is widespread and has been postulated to drive major transitions in evolution. A cooperator pays a cost to benefit others, and when reciprocated, it gains a net benefit. However, Darwinian selection favors "cheaters" that consume benefits without paying a fair cost. Many cooperative systems have evolved sophisticated cheater recognition/exclusion mechanisms. How did cheater-resisting mechanisms evolve from simple cooperative systems? To address this question, I created a genetically tractable cooperative system that can be observed as it evolves, step-by-step, from its inception toward increased stability. It consists of two engineered, nonmating yeast strains–a red-fluorescent R strain that requires adenine and releases lysine and a yellow-fluorescent Y strain that requires lysine and releases adenine. I observed that: 1) the system is viable, able to grow from low density to saturation in the absence of adenine and lysine supplements, over a wide range of conditions; 2) system viability requirements could be calculated from growth, death, and metabolic properties of the two cooperating strains; and 3) the system evolved increased system viability, with the minimum cell density required for system viability reduced 100-fold. My group will: 1) Discover the diversity of changes that increase system viability. Pro-cooperation changes must act through benefiting self and/or partner. Properties of evolved strains will be measured and their relative contributions to enhanced cooperation will be quantified. 2) Determine mechanisms of cheater tolerance. After introducing a cheater that consumes but does not release metabolites, we will select for cooperator/cheater cocultures with increased cheater tolerance and delineate mechanisms. 3) Investigate the possibility of spatial structure stabilizing cooperation. We will compare viability requirements and cheater tolerance of the cooperative system in a well-mixed liquid culture (no spatial structure) with those on an agar pad (with spatial structure). We hope to quantitatively understand the evolution of cooperation and cheater tolerance.
Justin L. SonnenburgStanford University School of Medicine
Project Title: Discovery of Gut Microbiota-Targeted Small Molecules: New Tools and Therapeutics
Grant ID: DP2-OD-006515
The composition and function of the human intestinal microbiota is tightly linked to diverse aspects of host biology. Several diseases, including obesity and inflammatory bowel diseases, have been associated with altered microbiota composition. While much research is currently aimed at a genomic definition of the microbiota in both healthy and diseased states, there is a paucity of studies aimed at understanding this community at a mechanistic and ecological level and how changes in its function and composition directly impact host biology. The question of whether disease-associated alterations in microbiota composition are a cause or symptom of disease is difficult to address due to the current lack of tools that allow us to test the effect of perturbations in microbiota structure and function on the host in a controlled experimental setting. And once we are able to identify a pathologic microbiota definitively, how will we return it to a healthy state? The goal of this research proposal is to identify small molecules that can alter the microbiota at the level of function and composition, providing: 1) tools to aid investigation of altered microbiotas in model organisms and 2) a model pipeline for identifying a new class of therapeutics that targets the intestinal microbiota. The ability to monitor host responses in gnotobiotic mice colonized with a normal human gut microbiota provides an unprecedented capacity to search for compounds that will be useful in human medicine. While others have speculated on the promise of targeting the microbiota to manipulate human health, specific plans of how this would be achieved are lacking. This proposal lays out a plan to screen for compounds that target specific taxa of the microbiota, characterize the targeted microbiota in vivo, and determine the impact on host biology.
Sohail TavazoieRockefeller University
Project Title: The Discovery of MicroRNAs That Predict Chemotherapeutic Responsiveness of Cancer
Grant ID: DP2-OD-006506
The vast majority of cancer deaths result from the metastatic spread of cancer cells to distal organs. Systemic chemotherapy can prevent metastasis in some patients by killing microscopic tumor cells throughout the body. Chemotherapy can also dramatically reduce the size of metastases in some advanced-stage patients. Interestingly, these standard chemotherapeutic regimens are administered to hundreds of thousands of patients without prior knowledge of the sensitivity of individual patients’ cancer cells to such treatments. If we could identify the chemotherapeutic responsive and resistant subsets of patients at diagnosis, innumerable patients would be spared from the risks, side effects, and expense of ineffective chemotherapy and instead offered alternative and experimental therapies in the upfront setting. Furthermore, the identification of such biomarkers could provide mechanistic insights into the molecular underpinnings of chemotherapeutic resistance. Working in breast cancer, we recently discovered a set of human microRNAs that strongly suppress metastasis in a robust mouse model of breast cancer. These microRNAs act as biomarkers since their expression levels in primary tumors predict future metastatic relapse, thus guiding clinical decision-making. Colorectal cancer is a highly prevalent and aggressive disease entity with significantly fewer treatment options than breast cancer. We propose to apply a conceptually and technically innovative, systematic, and multidisciplinary approach to discover chemotherapeutic-response predictive microRNAs through an experimental approach that integrates molecular, in vitro, in vivo, and human clinical insights. We will validate the power of these microRNA biomarkers through prospective in vivo human studies. If successful, we envision this powerful approach applied to other common cancers. The identification of such microRNAs will not only be of tremendous clinical value now, it will also lay the foundation for future mechanistic and synthetic efforts aimed at generation of novel, microRNA-based therapeutic agents for the prevention and treatment of cancer metastasis.
Jerilyn A. TimlinSandia National Laboratories
Project Title: Multiplexed Measurements of Protein Dynamics and Interactions at Extreme Resolutions
Grant ID: DP2-OD-006673
My goal is to develop state-of-art imaging technology that can measure protein complex formation and protein networks in a multiplexed fashion with spatial resolution beyond that of optical microscopy. At present, a major limitation to clarifying the dynamics of a particular signaling cascade is the inability to visualize multiple (>4) proteins and their interactions simultaneously in real time in the living cell. This is due in part to the interference of spectrally similar species (including cellular auto fluorescence) and the mismatch between the spatial resolution of the confocal microscope and the scale of protein interactions. Computational and experimental approaches can help to elucidate many of these interactions, but not all. Specialized microscopy methods have been developed to address some aspects of the problem, but to date, no technology has demonstrated true multiplexed (simultaneous, not sequential) detection of >4 proteins and their complex formation in living cells at spatial resolutions >100 nm. This type of detection is critical for unraveling protein interaction network details, and my proposed work will address that. Specifically, I will: 1) implement novel emission-scanning hyperspectral confocal microscopy hardware to collect information from large numbers of fluorescent species simultaneously at spatial resolution beyond that of the optical microscope, and 2) develop corresponding algorithms to spectrally unmix the 6D (X, Y, Z, excitation l, emission l, and time) ../images and provide accurate measurements of fluorophore concentrations even in the presence of energy transfer. This creative approach alleviates limitations of existing multicolor technology by extending my expertise in live-cell, hyperspectral imaging technology into the "super-resolution" realm. Its success will be enabled by robust, multivariate image analysis algorithms. This advance will have far-reaching impact in exploring signaling pathways and networks in biology and biomedicine.
Cho-Lea TsoUniversity of California, Los Angeles
Project Title: Cellular Quiescence and Brain Tumor Stem Cells
Grant ID: DP2-OD-006444
The discovery of tumor stem cells in human brain tumors has greatly changed the biological and clinical views of treatment-refractory brain cancer. Targeted therapies causing tumor stem cells to differentiate, undergo apoptosis, or die therefore represent a novel therapeutic strategy to treat recurrent tumors. The goals of this proposal are to identify genes that confer the tumor stem cell quiescence and to develop new brain tumor therapies based on the blockade of cellular quiescence in order to potentiate the treatment efficacy of radiation and chemotherapy. We have established several tumorigenic CD133+ glioblastoma (GBM) stem cell lines, which are directly derived from patients’ primary tumors that are recurrent and had previous treatment. Functional and molecular studies revealed that the slow-growing CD133+ GBM stem cells expressed a series of tumor suppressor/quiescence-associated genes but are capable of clonal self-renewal and spontaneous re-entry to the cell cycle to generate highly proliferative CD133- progeny that can populate tumor spheres in cultures and reconstitute a malignant tumor in mouse brain. We therefore hypothesize that GBM stem cells use reversibility of cellular quiescence to escape treatment followed by regenerating a new tumor upon treatment removal. We will perform a loss-of-function RNA interference screen for molecular targets of GBM tumor stem cell quiescence and test whether knockdown of quiescence factors will improve the treatment efficacy of radiotherapy and chemotherapy. Thus, the innovative treatment strategy proposed here aims to redirect reversible, viable arrested tumor stem cells toward non-reversible senescence, apoptosis, or terminal differentiation upon radiotherapy or chemotherapy. Preventing tumor stem cells from re-entering the cell division cycle after treatment shall greatly diminish the recurrence rate of GBM tumor.
Erik M. UllianUniversity of California, San Francisco, School of Medicine
Project Title: The Role of Astrocytes in Plasticity and Disease
Grant ID: DP2-OD-006507
Astrocytes are the most abundant cell type in the human brain, yet we still do not fully understand the impact of astrocytes on human disease. In this proposal we will begin to uncover the role of astrocytes in regulating cortical plasticity using several new technologies, including quantitative mass spectroscopy and microfluidic chambers developed to rapidly identify astrocyte factors that are released in response to the paracrine signals acetylcholine (ACh) or norepinephrine (NE) and that are likely to impact plasticity in both the developing and adult brain. Additionally, we will take advantage of the outstanding stem cell and proteomic centers here at UCSF to ask whether astrocytes derived from somatic cells from individuals on the autism spectrum secrete altered levels of synaptogenic factors. Using a combined microfluidic chamber and imaging system we will screen for effects on synapse formation and function using astrocytes derived from autism patients and familial controls. These studies have the potential to uncover the role of glial cells both in regulating normal plasticity and in disease states.
Vaiva VezysUniversity of Minnesota Medical School
Project Title: Understanding the Persistence of Immune-Mediated Chronic Diseases
Grant ID: DP2-OD-006473
Autoimmunity and asthma are immune-mediated diseases which can last for the lifetime of an individual, causing financial, physical, psychological, and societal burdens. Many of these diseases are characterized by symptomatic periods or flares, followed by a time of remission. Multiple factors, such as stress and infections, are believed to be responsible for this pattern. During these diseases, T cells are persistently stimulated by self or environmental antigens. Like autoimmune diseases, exposure to pathogens, which cause a chronic infection, also results in constant T cell stimulation by persistent antigens. I have recently demonstrated that new, pathogen-specific T cells are constantly produced during the chronic phase of infection, well after the initial infectious burst has resolved. This continued thymic output was required for maintaining the immune response. As common features can pertain to different immunological situations, the hypothesis to be tested in this proposal is whether the generation of T cells specific for tissue and environmental antigens in autoimmunity and asthma during established disease is a factor responsible for perpetuation of tissue damage. This hypothesis will be tested in different models of diabetes, multiple sclerosis, and a novel model of asthma. In addition, manipulation of thymic output during these chronic diseases, as well as during chronic infections, will determine whether newly developed T cells can be programmed to dampen atopic or autoimmune diseases or augment antimicrobial immunity. If successful, these studies may offer a novel explanation for the chronicity of certain immunological diseases and provide a new paradigm on which to base therapeutic intervention.
Leor S. WeinbergerUniversity of California, San Diego
Project Title: Developing Transmissible Antivirals by Exploiting Gene-Expression Circuitry
Grant ID: DP2-OD-006677
Emerging and established viral diseases take an enormous toll on human health. Current treatment approaches are unlikely to halt epidemic spread of many viruses, notably HIV-1, due to prohibitive costs of treatment (i.e., access), compliance issues, rapid viral mutation, and the influence of hard-to-reach high-risk viral “superspreaders.” We propose to shift the treatment paradigm toward developing Therapeutic Infectious Pseudoviruses (TIPs) that require the pathogen to replicate. TIPs would transmit along a pathogen's normal transmission route, reaching precisely those high-risk populations that most require therapy. TIPs co-opt wild-type virus packaging elements, decreasing disease-progression in vivo and reducing disease transmission on a population scale. We have demonstrated that an anti-HIV TIP could mutate with equal speed and under evolutionary selection to maintain its parasitic relationship with wild-type virus, thereby overcoming viral mutational escape. Since TIPs replicate conditionally (i.e., piggyback), treatment compliance and cost issues are eliminated. A precedent for the safety of TIPs exists in the oral polio vaccine (a live-attenuated vaccine), which exhibits limited spread and is being used in the polio eradication campaign. To develop candidate TIPs, we will capitalize upon our expertise in HIV-1 transcriptional circuitry. We discovered that HIV-1 exploits stochastic gene expression to control entry into a dormant state (proviral latency). By targeting a cellular gene (SirT1) essential for viral feedback, we have biased HIV-1 toward dormancy and diminished reactivation. We will exploit this innovative strategy of forcing viruses into dormancy by utilizing our single-cell imaging methods to conduct high-throughput imaging screens for therapeutic candidates that promote viral latency. Next, these candidate TIPs will be analyzed in novel microfluidic chemostats that maintain homeostatic infection and allow viral evolution in an in vivo-like setting. By integrating these approaches with predictive models, we will develop a revolutionary therapy to halt the spread of HIV/AIDS and other infectious diseases.
Chun-Li ZhangUniversity of Texas Southwestern Medical Center
Project Title: Neurogenesis De Novo in the Adult Central Nervous System
Grant ID: DP2-OD-006484
Trauma, stroke, and neurodegenerative disease result in neuronal loss, which leads to morbidity and mortality. A major advancement to mitigate these conditions would be to harness the ability to regenerate lost neurons. Although neural stem cells (NSCs) and neurogenesis normally exist in adult brain, the scarcity and restricted localization render them inadequate for regeneration. Cell transplantation is currently the strategy of choice to deliver new neuronal cells, but this approach is inefficient and cumbersome due to limited cell survival and poor integration into the functional neural networks following transplantation. In a highly novel approach to adult neurogenesis studies based on recent findings, we hypothesize that endogenous glial cells can be directly converted into neurogenic NSCs so that de novo-generated neurons will repopulate damaged brain regions. This hypothesis is based on our extensive studies using an essential nuclear receptor for NSCs and on the recent advancement of induced pluripotent stem (iPS) cells. We previously revealed that nuclear receptor TLX is not only essential for adult neurogenesis but is also sufficient to convert differentiated astrocytes into NSCs in culture. Although somatic cells from various tissues can be reprogrammed to iPS cells, it is not clear whether somatic cells can also be directly induced to form NSCs and neurons. Through transcriptional reprogramming, we propose to convert astrocytes and microglia, the two most proliferative glia cells during CNS damage, into NSCs and neurons. Using regulated expression of TLX in cultured cells and in transgenic mice, we will induce astrocytes to become proliferative, multipotent NSCs and then differentiate them into neurons. In addition, by using combinations of transcription factors, we will directly reprogram astrocytes or microglia to NSCs in cell culture and in adult mouse brains. Our long-term goal is to repopulate the damaged CNS regions using the patient’s endogenous non-neuronal cells.
Zev BryantStanford University
Project Title: Engineering Molecular Motors
Grant ID: DP2-OD-004690
Molecular motors lie at the heart of biological processes from DNA replication to cell migration. The principal goal of my research is to understand the physical mechanisms by which these nanoscale machines convert chemical energy into mechanical work. I propose a radical change in the way my laboratory approaches this goal. We will rigorously challenge our understanding of the relationships between molecular structures and mechanical functions by rationally engineering molecular motors with novel properties. The performance of our designs will illuminate both the inner workings of natural biological motors and the general operational constraints for producing directed motion on the molecular scale. Ultimately, construction of molecular motors to arbitrary specifications will provide a powerful toolkit for synthetic biology, therapeutics, and nanotechnology. My laboratory will design and characterize molecular motor variants using a rapid testing cycle that relies on new instrumentation for high throughput single molecule tracking and manipulation assays. We will focus our efforts by choosing a small number of ambitious design targets, each requiring several intermediate molecular innovations and optimizations. For the period of this award, two initial design targets will be pursued, leveraging our existing expertise in myosin and topoisomerase mechanochemistry. Success will represent an unprecedented level of control over nanoscale motion, building an engineering capacity that will eventually be used to design protein nanoassemblies capable of sophisticated intracellular therapeutic functions such as genome repair. Novel molecular motors will also have ex vivo applications including molecular sorting and assembly of nanoelectronics in microfabricated devices.
Ronald J. BuckanovichUniversity of Michigan at Ann Arbor
Project Title: Using Embryonic Stem Cells to Re-Create a Human Tumor Microenvironment to Develop Ovarian Cancer Therapeutic and Diagnostic Tools
Grant ID: DP2-OD-004197
Tumor vasculature expresses unique markers that represent novel immunotherapeutic targets. Development of anti-vascular immunotherapeutics, with few exceptions, has been hindered by the absence of a tumor model with human tumor vessels. A new tumor model, combining human embryonic stem cells (ESC) and tumor cells, develops abundant human vessels. It is unknown if these are ‘normal’ or ‘tumor’ vessels, expressing tumor vascular markers (TVMs). We hypothesize that ovarian cancer cells will induce human ovarian TVM expression. We propose (1) to characterize ovarian TVM expression in an ESC-ovarian cancer model for the development of anti-vascular immunotherapeutics. We recently identified over 70 ovarian TVMs. Many ovarian TVMs are not expressed in normal tissues or other tumors. Tumor specific expression, expression at the earliest stages of tumor development, and direct exposure to blood, suggest that TVMs are ideal biomarkers for both ovarian cancer diagnosis and targeted immunotherapy. We propose (2a) to test anti-ovarian TVM antibodies as diagnostic tools and, (2b) to couple anti-ovarian TVM antibodies with toxic nanoparticles and test them as immunotherapeutics using the ESC ovarian tumor model. Finally, our preliminary data suggest that the ESC-ovarian tumor model has human tumor vascular cells. Tumor vascular cells are critical for the growth of tumor stem cells, which reside within the vascular niche. One challenge with characterizing tumor stem cells has been finding appropriate conditions for in vivo growth. We hypothesize that the ESC ovarian tumor model, with human vascular cells, will provide an ideal microenvironment to support human stem cell growth. We therefore propose (3) to isolate ovarian tumor stem cells and grow them in vivo using the ESC ovarian cancer model. If successful, this will create a murine tumor model that nearly completely reproduces the human tumor microenvironment with human tumor stroma, vessels and tumor stem cells.
Timothy J. CardozoNew York University School of Medicine
Project Title: Chemical Biology Design for Malaria
Grant ID: DP2-OD-004631
An effective molecular design successfully captures the balance, proportion and rhythm of a specific biomolecule while respecting the unity of the biomolecule with its cellular, tissue, whole organism and ecological surroundings. I propose to lead the design of a drug that crosslinks two proteins of the gliding motility machinery of P. falciparum: the causative agent of malaria. This molecule will be a novel malaria treatment operating directly at the complicated host-pathogen interface and influencing the enormous global health burden of this disease. First, the inter-locking parts of the gliding motility machinery will be visualized by a combination of novel molecular modeling approaches and X-ray crystallography. Of note, three-dimensional visualization of the first interlocking part failed via either of these approaches separately, but we succeeded by cleverly deploying them in an integrated fashion. Additional interlocking pieces of the gliding motility machine are already being unveiled by this unique approach, so we are confident that we can visualize the intricacies of a large bloc of the molecular machine in its in situ configuration. Second, exploitable pockets in the whole machine will be targeted for drug design via a combination of in silico screening of chemical databases and novel cheminformatics techniques. We describe how this integrated approach revealed a hitherto unrecognized “druggable” site, allowing the biology to guide the design.
Karen L. ChristmanUniversity of California San Diego
Project Title: Engineering a Dynamic Extracellular Matrix Microenvironment
Grant ID: DP2-OD-004309
In the fields of biomaterials and tissue engineering, the ability to modulate cell behavior on surfaces is essential, particularly when attempting to direct cell growth and differentiation, both for in vitro engineered tissue and generating cell sources from progenitors and/or stem cells. A major area of work in tissue engineering is the development of artificial extracellular matrices or scaffolds. The extracellular matrix in vivo is a dynamic entity that often shifts between a composition of one distinct set of components to another. This matrix remodeling is especially common during development, differentiation, and wound repair. A dynamic engineered matrix that emulates this situation in vitro has yet to be developed and would have a huge impact in tissue engineering and regenerative medicine. For example, one of the biggest challenges to realizing stem cell therapies is the ability to take a premature cell and differentiate it into the desired phenotype. While soluble factors and static matrices have been examined for accomplishing this goal, the technology that could mimic the developing extracellular matrix, which is known to regulate cell survival, migration, proliferation, and differentiation, has not been developed. The principal investigator aims to create such a dynamic matrix microenvironment that could promote differentiation by mimicking extracellular matrix morphogenesis. Therefore, differentiated cell sources from progenitors and stem cells could be more efficiently obtained, which would have direct impact on promoting and advancing cell therapies, including engineered tissue. This work will be enabled by a novel and innovative, multi-layer format patterning technique developed by the principal investigator.
Brian A. CobbCase Western Reserve University
Project Title: T Cell Dependent Immune Responses to Carbohydrate Antigens
Grant ID: DP2-OD-004225
Over the past decade, disparate infectious and non-infectious diseases ranging from cancer and autoimmunity to bacterial and viral infections have been tied together through the common involvement of sugar moieties. For many years adaptive immunology has maintained a model in which peptides are the only specific antigens that are presented via the major histocompatibility complexes to T cells, and are therefore required components for vaccine and immunotherapeutic applications. In the last several years, I have demonstrated that at least one class of carbohydrates can also be presented by MHC molecules, thus shifting the longstanding “peptide only” paradigm of MHC presentation. This work was the subject of an article published in Cell and leads to my hypothesis that glycans are capable of inducing clonal expansion of a specific T cell subset that recognizes MHCII/glycan complexes. I propose to create the first glycan-MHC tetramer and to use this reagent to determine if clonal expansion of carbohydrate-reactive T cells occurs. If successful, the findings would re-define the current T cell recognition paradigm to include carbohydrates as specific MHCII-dependent stimulators of adaptive immunity, thus opening the door to new immunotherapeutic possibilities. Construction of a glycoantigen/MHC tetramer will also open up the power of the tetramer technique (the original report with peptide antigens has been cited 1877 times to date) to the study of the glycome and utilize the enormous advances that are occurring in our understanding of cell glycans to enable identification of glycan-induced immune responses. As such, I believe this proposal represents the ideal combination of attributes suitable for the DP2 funding mechanism (Section 05: Immunology) through the Office of the Director since our findings could hold profound implications for human health across traditional institute barriers through the creation of vaccines and/or immunotherapeutics targeting specific carbohydrate epitopes in the treatment of cancer, autoimmunity and a host of infectious diseases.
Ronald D. CohnJohns Hopkins University
Project Title: Maintenance of Skeletal Muscle Mass: Lessons Learned from Hibernation
Grant ID: DP2-OD-004515
Skeletal muscle is the largest organ in the human body comprising ~50% of the body’s weight. Maintenance of normal muscle mass and physiology is essential for health. Disuse (e.g., immobilization, denervation, and microgravity) and aging result in debilitating loss of skeletal muscle. An estimated $26 billion dollars of annual health care costs are attributed to complications directly associated with age-related loss of muscle mass alone. This does not account for the cost of the plethora of clinical diseases including cancer, sepsis, diabetes, AIDS, and neurodegenerative disorders which are associated with varying degrees of muscle atrophy and dysfunction. Satellite cells are primary stem cells in adult skeletal muscle and are responsible for the postnatal maintenance, growth, repair, and regeneration of skeletal muscles. Loss of muscle mass is the net result of a decrease in satellite cell number and/or impaired proliferation, associated with increased muscle proteolysis and decreased protein synthesis. In stark contrast to the above, hibernating mammals have evolved mechanisms to survive prolonged immobility without pathologic loss/atrophy of muscle mass. The molecular mechanisms underlying this fascinating phenomenon are largely unknown. This innovative and novel project will for the first time apply knowledge of normal mechanisms of muscle protection in the hibernating mammal to the disease process of disuse muscle atrophy in nonhibernating mammals. This will provide unique insights into the fundamental cellular and molecular pathways underlying skeletal muscle atrophy and the protection against it. The proposed in-depth investigation of satellite cells provides the first analysis of a stem cell in any hibernating animal. Furthermore, applying the novel gene expression-based high-throughput screening approach will enable the identification of drugs which may provide novel therapeutic interventions for a broad group of patients with skeletal muscle atrophy and degeneration.
Xiangfeng DuanUniversity of California Los Angeles
Project Title: Integrated Free-Standing Nanoprobes for Neuroscience and Beyond
Grant ID: DP2-OD-004342
A central theme of this proposal is to explore the unique capabilities of nanotechnology to create novel neuroprobes that can break the boundaries of traditional technologies, and revolutionize our basic understanding, visualization and therapeutics of neural systems. A new concept of freestanding integrated nanodevice has been proposed, in which all necessary functional components are integrated in a single nanostructure to form a standalone active device. This device format will therefore enable an entirely new generation of true nanoscale devices that can function as minimally invasive biological nanoprobes for detecting, monitoring and manipulating neural activities and electrophysiological signals with unprecedented sensitivity, spatiotemporal resolution and throughput. Systematic studies will be carried out to synthesize this new type of nanoprobes with optimize performance, understand their fundamental device function, and investigate their applicability as highly sensitive in vitro and in vivo biological nanoprobes. The successful development of such nanoprobes will herald the beginning of a new paradigm for nanoscale devices and minimally invasive biological nanoprobes, and can impact broadly from basic neuroscience to novel approaches for medical diagnostics and therapeutics.
Seth J. FieldUniversity of California San Diego
Project Title: Phosphoinositides Provide Unique Insights into Cell Biology and Pathophysiology
Grant ID: DP2-OD-004265
The phosphoinositides are a group of lipid signaling molecules that are known to play critical roles in regulating cell proliferation, apoptosis, metabolism, autophagy, signal transduction, and membrane trafficking. They play important roles in the pathophysiology of inflammatory disease, cardiovascular disease, neurologic disease, type 2 diabetes mellitus, and many cancers that together afflict the majority of Americans. Understanding the phosphoinositides is key to understanding a wide range of cell biology and human pathophysiology. Nevertheless, our understanding of their range of functions and mechanisms of action remains rudimentary at best. Here, I propose to develop three novel approaches to study the phosphoinositides in a systematic and unbiased way. The three approaches together provide tremendous synergy. Using these novel approaches my preliminary data has already identified new, surprising functions for the phosphoinositides. Once systematically applied, these approaches have the real potential to revolutionize our understanding of the functions of the phosphoinositides and the diverse biological processes and disease states that they control.
Zemer GitaiPrinceton University
Project Title: Discovering Antibiotic Drugs & Targets Via High-Throughput Bacterial Cell Biology
Grant ID: DP2-OD-004389
The rise of antibiotic resistance in bacterial pathogens represents an escalating global health crisis. We will help tackle this problem by applying our expertise in high-throughput imaging and bacterial cell biology to identify and characterize both new families of proteins essential for bacterial viability (candidate drug targets) and small molecules that perturb these proteins (candidate drugs). This proposal builds upon our previous development of methods to analyze protein localization that are fast, easy, and affordable enough to be routinely re-applied on a genomic scale. We have already used this high-throughput pipeline for generating, imaging, and quantitatively analyzing fluorescent protein fusions to determine the localizations of over 3,250 proteins in Caulobacter crescentus, a unique polarized model bacterium, identifying over 300 new localized proteins. We now propose to harness these resources to identify new antibiotics and antibiotic targets. First, we will combine our localization library and high-throughput imaging methods to screen for antibiotic compounds that inhibit the localization and function of known essential localized proteins, such as bacterial cytoskeletal elements. As a promising proof of principle, we have characterized a small molecule that targets the bacterial actin-like cytoskeleton and can block the growth and virulence of a wide range of human pathogens. We will use our new methods for high-throughput high-resolution microscopy to screen for compounds that perturb the localization of the MreB actin homolog, the FtsZ tubulin homolog, and the ParA cytoskeletal ATPase. These proteins are all localized, essential, and very widely conserved among human pathogens. Second, we will combine our recently-completed screen for new localized proteins with traditional molecular genetic techniques to identify and characterize novel families of proteins that are localized, conserved in pathogens, and essential. These proteins will represent excellent targets for future chemical screens to find new classes of antibiotic compounds.
Aaron D. GitlerUniversity of Pennsylvania
Project Title: Using Yeast Cells to Define Mechanisms of Human Neurodegenerative Diseases
Grant ID: DP2-OD-004417
The United States and other countries around the world are experiencing a demographic sea change owing to the rapidly growing elderly and ‘Baby Boomer’ populations. As our population continues to age, neurodegenerative disease will increase in prevalence and thus pose a daunting challenge to public health worldwide. These truly disastrous disorders include Alzheimer’s, Huntington’s, Parkinson’s, amyotrophic lateral sclerosis and the frontal temporal dementias. Interestingly, though disparate in their pathophysiology, many of these diseases share a common theme manifest in the accumulation of insoluble protein aggregates in the brain. The long-term goal of my laboratory is to elucidate the mechanisms causing these proteins to misfold and aggregate, identify the genes and cellular pathways affected by misfolded human disease proteins, and understand their function in normal biology. We are taking an innovative approach to attacking this exceedingly difficult problem: harnessing the baker’s yeast, Saccharomyces cerevisiae, as a model system to study the mechanisms underpinning protein-misfolding diseases. Surviving cellular stresses caused by misfolded proteins is an ancient problem that all cells struggle with and many of the mechanisms employed to deal with protein misfolding are conserved from yeast to man. We propose to create yeast models of human neurodegenerative diseases and to perform high-throughput genome-wide screens to elucidate the basic cellular mechanisms of toxicity. These yeast models will provide us with a unique opportunity to observe and understand protein folding and misfolding in real time as it occurs in a living cell and then to ask big questions on a genomewide scale about the cellular pathways affected by the aberrant accumulation and/or function of human disease proteins. We hypothesize that the mechanisms identified by our studies will have broad applicability to multiple neurodegenerative diseases. The innovative aspect of our approach is not just that we are working in yeast, but that we are willing and able to use this system as a discovery tool, which we will validate in more relevant animal models. We have done this successfully in the past (via collaboration and on our own) and this will allow us to proceed with future experiments from a knowledgeable point of view, knowing the relative strengths of various organisms and methods.
David H. GraciasJohns Hopkins University
Project Title: Minimally Invasive Micro-Nanoscale Tools and Devices for Medicine
Grant ID: DP2-OD-004346
We propose to develop a new class of minimally invasive micro-nanoscale surgical tools and biomedical devices using a new strategy developed in our laboratory that is based on the self-actuation and self-assembly of lithographically patterned templates. Recently, we fabricated the first-of-their-kind, mass producible, mobile grippers and demonstrated the capture and retrieval of microscale objects without batteries, wiring, or tethers. In contrast with present day endoscopy tools that utilize tethers (and hence are difficult to manipulate around corners and in coiled geometries), the mobile grippers were used to demonstrate the first tetherless, remotely guided, in vitro biopsy within a narrow tube. We plan to build on these preliminary results to develop an entire mobile and remotely actuated toolbox (including grippers, cutters and locomotors) for microsurgery. We have also engineered a new class of remote controlled containers for in vitro lab-on-a-chip applications and in vivo drug delivery. The devices are small enough to fit through a hypodermic needle, thereby facilitating minimally invasive implantation and guidance in hard to reach micro-spaces. We propose to advance the functionality of these self-loading miniaturized containers by incorporating modules for sensing, imaging and telemetry within them. Our research goals are unique in that we seek to utilize mechanisms for motion and assembly that are harnessed within the structure, obviating the need for external tethers. Hence, apart from being technologically relevant, these paradigms are intellectually stimulating as they also enable the possibility for autonomous control of miniaturized machine-based function in human engineered biomedical systems.
Christy L. HaynesUniversity of Minnesota Twin Cities
Project Title: Immune System-on-a-Chip for Quantitative Analysis of Cell Interactions During Allergy Response
Grant ID: DP2-OD-004258
The human immune system is an elaborate and dynamic network of cells, tissues, and organs responsible for protecting us from disease. Understanding the fundamental cellular interactions in vivo during immune response is a daunting task based on the inherent complexity of similar but distinct cell types and the diverse signaling pathways between these cells. The work proposed herein exploits a bottom-up analysis strategy, first using microelectrochemistry techniques to quantitatively characterize chemical messenger secretion from individual immune cells in real time, then characterizing how this degranulation response changes with controlled exposure to various triggering molecules and chemokines, and finally assembling a simplified immune-system-on-a-chip where direct cell-cell communication can be measured, controlled, and manipulated. This work will reveal both useful fundamental information about chemical messenger packaging and delivery in immune system cells and illuminate the mechanism of and possible therapeutic approaches to Type I hypersensitivity using the interconnected chip-based format. This work is particularly well-suited to the NIH New Innovator funding mechanism based on the fact that this is a high risk-high reward project that, if successful, will have a major impact on biomedical science. Additionally, this interdisciplinary approach, requiring not only nontraditional methods but also a paradigm shift where immune cell interactions are considered from a bottom-up perspective, can only be executed with significant financial support and the freedom to achieve great results based on encouraged innovation and creativity. The risk of this innovative proposal is mitigated by the fact that initial experiments commence directly from preliminary results in the Haynes laboratory and complexity is added at each major step. In addition, the principal investigator has a performance history of leveraging her expertise in an entirely new field, allowing her research group to approach scientific problems in a way nobody else is considering and provide insight with new perspective.
Shelli R. KeslersStanford University
Project Title: Assessment and Treatment of Cognitive Deficits in Breast Cancer
Grant ID: DP2-OD-004445
Some studies indicate that breast cancer (BC) survivors are at significant risk for long-term cognitive deficits. Increasing BC survival rates may thus result in a large and rapidly growing cohort of women with extended disease-related disability. Adjuvant chemotherapy may be a significant contributing factor to cognitive impairments in BC. However, the role of chemotherapy in BC cognitive outcome is controversial. The specific cognitive deficits in BC, their incidence and underlying mechanisms are largely unknown due to a paucity of research in this area. There currently are no treatments for cognitive deficits related to BC. The goals of the proposed research are to 1) define the specific cognitive deficits associated with BC and chemotherapy using comprehensive, ecologically valid neuropsychological assessment, 2) elucidate the neurobiologic states underlying cognitive impairments in women with BC using advanced neuroimaging techniques, 3) identify demographic, medical and genetic factors associated with cognitive outcome in BC, and 4) test the efficacy of two innovative treatment methods – one for improving existing cognitive impairments and the other for preventing cognitive impairments. The proposed research will implement highly innovative methods including measurement of hippocampal neural stem cells, using neurofeedback as a preventative treatment method and evaluating a combination of genetic variants believed to influence cognitive outcome. Results of this project will provide prognostic information regarding treatment options for cognitive effects of BC, will address the lack of treatment methods for cognitive impairments in general by providing a new model of cognitive rehabilitation, and will increase our understanding of neural injury, recovery and repair. Additionally, cancer in general affects millions of individuals – males and females of all age groups, socioeconomic strata and ethnicities. Therefore, results from this project may have broad applications by providing direction for studies of cognitive effects in other cancers and conditions treated with chemotherapy.
Yuriy KirichokUniversity of California San Francisco
Project Title: Molecular Biophysics of Mitochondrial Membranes: Defining Future Therapeutic Targets
Grant ID: DP2-OD-004656
Mitochondrial dysfunction is implicated in several devastating diseases, such as neurodegeneration, obesity, diabetes, and cancer. Pharmacological interventions at the level of mitochondria can become an effective way to treat these pathological conditions. However, the development of such therapeutic tools is prevented by our incomplete understanding of the molecular mechanisms that underlie major mitochondrial functions, including energy production, setting the pace of aging, and controlling cell death. The transport of ions and molecules across the mitochondrial membranes is the foundation of the mitochondrial physiology and a lack of direct methods to study mitochondrial transmembrane transport is likely the most significant barrier to a better understanding of mitochondria. The key mitochondrial transport proteins, such as ATP synthase, the electron transport chain, and ion channels of the inner and outer mitochondrial membranes, could be best studied using the patch-clamp technique. This method revolutionized our understanding of ion channels and electrogenic transporters of the plasma membrane; however, an analogous application of the patch-clamp technique to mitochondria has been extremely difficult due to their small size and double-membrane architecture. Here we propose to develop an easily reproducible method for the application of the patch-clamp technique to both the inner and outer mitochondrial membranes for routine use in mitochondrial research. We will then apply the whole-membrane and single-channel modes of the patch-clamp technique to identify the full complement of ion channels and electrogenic transporters that are present in the inner and outer mitochondrial membranes. The accomplishment of these aims will provide an unparalleled functional essay for the key mitochondrial transport proteins, which, when combined with molecular biology, genetics, and protein crystallography, will facilitate significant advances in our understanding of the molecular workings of mitochondria and the subsequent development of therapeutic tools that control mitochondrial functions.
Sanjay KumarUniversity of California Berkeley
Project Title: Cellular Mechanobiology: Biophysics and Therapeutics
Grant ID: DP2-OD-004213
One of the most important lessons from cellular physiology in the past decade is that living cells sense, process, and physiologically respond to specific physical stimuli in their environment, including the geometry, dimensionality, and rigidity of the extracellular matrix (ECM). This has spawned an intense effort to understand how mechanical cues manifest themselves in the context of problems ranging from stem cell engineering to tumor growth to scar formation, which has collectively led to the genesis of a completely new field: Mechanobiology. Yet, despite this recent flurry of activity, the field of mechanobiology continues to suffer from two limitations which threaten to restrict its long-term progress: mechanistic disagreements about how cells sense and process mechanical cues, and uncertainty about whether mechanobiological relationships observed in vitro also operate in a more clinically relevant setting. Here I propose to advance the field of mechanobiology by addressing both of these issues, organizing my research around three questions. (1) How are intracellular and extracellular mechanical stimuli applied to microscale portions of a living cell chemically and physically communicated to the rest of the cell, and how do these signals physically trigger changes in gene programs? (2) How does the regulation of specific genes, gene networks, and signaling pathways differentially depend on physical cues from the ECM, such as ECM rigidity, geometry, and dimensionality, and can cells be genetically engineered to alter their responses to these cues? (3) Can targeting mechanobiological interactions between cells and the ECM influence tissue physiology and pathology in vivo? By directly tackling these questions, we will strengthen the mechanistic foundations of this nascent field and facilitate the creation of cellular engineering and therapeutic strategies which leverage its principles.
Chay T. KuoDuke University
Project Title: Discovering Pathways Regulating Neurogenesis and Brain Remodeling After Injury
Grant ID: DP2-OD-004453
Modern medicine has few treatment options for brain injuries. In many diseases, the most effective therapies are based on detailed knowledge of pathophysiology, but relatively little is known about how the central nervous system (CNS) responds to environmental changes induced by trauma or stroke. This lack of knowledge is central to why treatments for CNS injuries have lagged behind those available for other organ systems. The goal of my research is to understand how a seemingly mature nervous system responds to environmental challenges such as injury, and how neural stem cells participate in this process. Throughout development, neural stem cells give rise to differentiated neurons, astrocytes, and oligodendrocytes which together modulate perception, memory, and behavior in the adult nervous system. To understand how neural stem cells contribute to brain remodeling after injury, we focus on the subventricular zone (SVZ) of the lateral ventricles in the postnatal/adult brain, an area containing self-renewing stem cells that generate immature neurons throughout life. Current studies of SVZ neurogenesis and stem cell behavior after brain injury involve either fixed tissues from sacrificed animals, or dissociated cells cultured in vitro in the presence of serum and growth factors. Inconsistent findings from established laboratories have prevented neural stem cell research from rapidly moving beyond phenomenology into fulfilling their potential as endogenous therapeutic agents, and point to a clear need for better assays and tools. My laboratory has generated a novel method to both identify SVZ cells after brain injury and to image their behavior in intact brain tissue. The goal of this proposal is to use these novel techniques, in combination with innovations in optical engineering and chemical screening to advance our understanding of how tissue stem cells deal with environmental change, and to identify new therapeutic strategies for brain injuries.
Lara K. MahalUniversity of Texas Austin
Project Title: An Integrated Systems Approach to Deconstructing Glycosylation
Grant ID: DP2-OD-004711
This application is in the area of Chemical Biology (Area 2). Glycosylation, which creates a diverse array of carbohydrate epitopes attached to cell surface proteins and lipids, is an inherently complex system that is poorly understood. Carbohydrates play crucial roles in a diverse array of medically relevant biological processes from viral pathogenesis to tumor cell metastasis and stem cell differentiation. However, due to the biosynthetic and molecular complexity of these biopolymers, we have little comprehension of how glycan synthesis is controlled. Systems-based approaches to biology, in which large datasets are analyzed using bioinformatic algorithms, provide an important avenue for exploring the mechanics of complex systems that cannot be predicted a-priori. Application of such approaches to glycosylation however has been limited due to the lack of methodology for high-throughput analysis of carbohydrates (glycomics). Recent work in my laboratory on lectin microarray technology has begun to address the analytical problems inherent in glycomics and thus pave the way for systematic analysis of the glycome. I propose to use the NCI-60 cell panel as a model system to integrate glycomic information with proteomic, genomic and metabolic pertubation data to create a predictive model of how cell surface glycosylation is encoded. To achieve this objective, we will reinvent bioinformatics technology for glycomics including analytical and databasing methods, integration of information and predictive modeling, providing useful tools for the study of glycomics in a wide variety of contexts. Detailed knowledge of how the genome and other factors control glycosylation will have a strong impact on a diverse swath of fields where carbohydrates play important roles including immunology, cancer research and developmental biology and may impact their use as potential biomarkers for disease.
Coleen Tara MurphyPrinceton University
Project Title: Slowing the Ticking Clock: C. elegans Screens for Reproductive Aging Regulators
Grant ID: DP2-OD-004402
Human reproductive aging manifests itself in maternal age-related increases in infertility, miscarriage, and birth defects. We propose to develop methods to prevent and treat age-related reproductive problems. For this purpose, we have developed a C. elegans as a model of reproductive cessation, and we are using it to find mutants and chemical treatments that extend the reproductive period. The goals of our work are to (1) physiologically and molecularly characterize the cause of reproductive cessation in wild-type animals, (2) identify mutants that slow reproductive aging and maintain egg quality later in life, and (3) carry out a high-throughput screen for chemical compounds that slow reproductive aging. Thus far we have been able to determine the underlying cause of reproductive aging in C. elegans, decreased egg quality, which is also thought to be the underlying cause of human reproductive aging. Thus, our model has great potential to aid in the study of human reproductive aging. We have also identified a conserved TGF-ß pathway as a major regulator of reproductive aging, and have defined its downstream transcriptional effects. Finally, we have designed and carried out pilot screens to identify mutants with extended reproductive spans. In addition to the mutants we select in the screen, which represent possible new drug targets, we propose using a chemical genetic screen to identify candidate drugs for the treatment of age-related reproductive problems. Our screen will not only identify chemical compounds that can increase progeny viability, it will also determine the effect of these chemicals on the health of the mother. These approaches will expand our knowledge of the causes of reproductive aging, and will help identify candidates for the treatment and prevention of age-related reproductive decline.
Ken-Ichi NomaWistar Institute
Project Title: A New Methodology to Decipher Three-Dimensional Genome Structure
Grant ID: DP2-OD-004348
The eukaryotic genome is present in the nucleus as a complex three-dimensional (3D) entity, the structure of which is disorganized in certain human diseases including various cancers. However, it remains unclear how 3D genome organization influences pathological processes. One impediment is the lack of established methods to investigate higher-order genome organization in three dimensions. We propose to develop a new methodology to map the 3D structure of the genome in vivo. To accomplish this goal, we will first use the chromosome conformation capture (CCC) technique to acquire vast amounts of paired DNA fragments that reflect the physical interactions among multiple genomic loci. The CCC technique involves fixation of the in vivo genome structure by paraformaldehyde (pFA), followed by restriction enzyme digestion and DNA ligation. We will follow this with a newly developed Solexa sequencing technology, which can determine sequences for several million DNA fragments in one experiment. We will create a frequency distribution table indicating the physical interactions between DNA fragments based on the large-scale sequencing results, and model the global 3D genome structure using these data. To accelerate development of this innovative system, we will use the fission yeast Schizosaccharomyces pombe as a simple test model for our technology; then, we will apply this new method to the human genome by analyzing DNA fragments containing Alu repeats, since the human genome is too large to analyze in its entirety. By comparing 3D genome structures sampled from nondiseased and diseased individuals, we will demonstrate the involvement of higher-order genome disorganization in human diseases. This innovative method has the potential to elucidate a novel but poorly understood aspect of pathogenesis, and is also applicable for disease diagnosis by detecting subtle morphological alterations of nuclear structure in diseased individuals. Thus, it has the potential to directly and profoundly affect human health.
Melanie OhiVanderbilt University
Project Title: Multifaceted Approaches for Studying the Structure and Function of Spliceosomes
Grant ID: DP2-OD-004483
In this era of large-scale proteomic analysis it is apparent that proteins carry out cellular processes as members of dynamic multi-protein assemblies rather than simply working as isolated individuals. Technical advances in epitope tagging and mass spectrometry, as well as the use of genome-wide two-hybrid screens, have led to an explosion of data listing and mapping numerous protein-protein associations found with the cell. Although progress has been made cataloging the constituents of specific complexes, our understanding of how proteins assemble into higher order structures and how multi-protein complexes perform their cellular functions remains a significant challenge. Structural analysis of these proteins assemblies will be required to understand their organization and function. Single particle cryo-electron microscopy is a powerful structural technique that is uniquely suited for working with large dynamic complexes that are too difficult to crystallize. The spliceosome is a macromolecular machine that catalysis the excision of non-coding introns from a pre-messenger RNA (pre-mRNA). It is formed from five small nuclear ribonucleoprotein subunits (snRNPs) and numerous non-snRNP splicing factors. However, how the snRNPs are organized within a larger unit to execute the catalytic steps of pre-mRNA splicing is not known. Understanding how the spliceosome functions is important because many human diseases and some forms of cancer arise from pre-mRNA splicing errors. However, the large size and dynamic nature of spliceosomal complexes has made structural characterization extremely challenging. The goal of this proposal is to take an innovative multi-disciplinary approach to probe the structure and function of spliceosomal complexes. We will use cryo-EM in combination with yeast genetics and biochemistry to improve our understanding of how these very large, dynamic cellular machines are structurally organized and how this organization translates into function within the cell.
Karin S. PfennigUniversity of North Carolina Chapel Hill
Project Title: The Origins and Maintenance of Context-Dependent Behavior
Grant ID: DP2-OD-004436
Often, an individual’s behavior depends on its own condition and the environment in which it expresses that behavior. How and why such context-dependent behavior arises and is expressed remains relatively unknown. One common explanation for context-dependent behavior is that individuals who are in relatively poor condition, or are otherwise suffering from diminished perceptual or behavioral capabilities, are simply incapable of expressing normal behavior in some environments. While such constraints undoubtedly occur, this explanation does not satisfactorily account for predictable patterns of behavioral variation that are often observed among different populations or groups of individuals. The possibility that individuals who vary in genotype or phenotype might adopt alternative behavioral strategies in a given environmental context is emerging as the new frontier in behavioral research. Distinguishing between these alternative explanations is critical for understanding the origins of behavioral variation. Indeed, explaining how and why individuals express context-dependent behavior can help us understand and successfully intervene in behavioral disorders. Moreover, because behavior is often linked to the transmission and progression of disease, understanding the origins and maintenance of context-dependent behavior has far-reaching implications beyond behavior. I propose to adopt a novel model system that integrates the strengths of field biology with the power of the model system approach. By working with a system for which we understand the ecological context of the behavior as well as the evolutionary history of populations and species, I can examine what factors generate environmental sensitivity and evaluate the genetic and environmental factors that contribute to the maintenance and expression of condition-dependent behavior within and across populations. In particular, I will evaluate: the ecological conditions that promote environmentally sensitive behaviors; the genetic and neural mechanisms that underlie context-dependent behavior; and the environmental and cross-generational origins of variation in condition and its effects on behavior.
Miguel Ramalho-SantosUniversity of California San Francisco
Project Title: Role of Pluripotency in Development of the Germline
Grant ID: DP2-OD-004698
A fundamental question in Molecular and Cellular Biology (Area of Science #7) is how the differentiation potential of cells is regulated. Early embryonic cells are considered pluripotent because they can differentiate into all cell types of the body. However, most of the studies aimed at understanding pluripotency have been performed in vitro, using cultured Embryonic Stem (ES) cells. Few studies have addressed the question of the significance of pluripotency in vivo. We have made progress towards answering this question. Data from our laboratory indicate that there is a global maintenance of the transcriptional program for ES cell pluripotency in the embryonic germline in vivo. Little is known about how the germline is distinguished from somatic tissues. We will test the hypothesis that the pluripotency program is essential to repress somatic differentiation in the germline. Understanding how this program represses somatic differentiation will put us in a position to harness pluripotency for novel cell-replacement therapies for degenerative diseases. A major roadblock to the use of pluripotent stem cells in the clinic is that they give rise to germ cell tumors when injected into animals. Such tumors arise spontaneously from transformation of the germline. If the pluripotency program is central to germline identity, there must be mechanisms that keep this program under control to prevent germ cell tumorigenesis. We propose to identify these mechanisms, based on insights provided by our current data. If this research is successful, we will have uncovered routes towards preventing ES cell-induced tumorigenesis and potentially reversing the course of testicular cancer. To accomplish these goals, we are developing innovative methods for rapid germline-specific and drug-inducible genetic manipulations in the mouse. Our trajectory is aimed at deciphering the biological significance and molecular regulation of pluripotency, towards making the use of pluripotent stem cells in regenerative medicine a reality.
Samara L. Reck-PetersonHarvard University (Medical School)
Project Title: Cellular Control of Microtubule-Based Transport: Unraveling Its Molecular Mechanism
Grant ID: DP2-OD-004268
The microtubule (MT) cytoskeleton and the molecular motors that move along it—dynein and kinesin—are responsible for powering the movement of chromosomes during mitosis and of organelles, signaling molecules and RNAs in the cytoplasm. The spatial and temporal regulation involved in transporting these cargoes at the cellular level remains one of the big unsolved questions in the field of cell biology. I propose to use the filamentous fungus, Aspergillus nidulans, as a model system to dissect the molecular mechanisms of MT-based transport, with a combination of approaches ranging from genome-wide screens to single-molecule biophysics. Aspergillus' polarized hyphae, whose rapid growth requires MT-based transport, and its high frequency of homologous recombination make it an ideal model organism for studying transport. Importantly, the number and types of cargo transporting motors present in Aspergillus are more similar to mammalian systems than to yeast-like fungi. We will identify all the organelles transported by the Aspergillus motors; this will constitute the first inventory of cargoes carried by MT-based motors in a single cell. After identifying these cargoes, we will create a complete gene disruption library that will be used to perform high-throughput microscopy-based screens to identify novel molecules required for dynein- or kinesin-based motility. In parallel with screening, we will purify the native Aspergillus motors and determine their properties in vitro using single-molecule motility assays. Hits from our screens that pass secondary rounds of screening will be tested in these assays for roles in regulating motor function or cargo binding. Ultimately, we aim to reconstitute motor-cargo transport in vitro and to develop methods to observe the dynamics of transport in vivo with nanometer precision. We expect to identify novel conserved paradigms regarding the mechanism of MT-based cargo transport.
Erik ShapiroYale University
Project Title: Single Cell MRI of Directed Cell Migration to Stroke
Grant ID: DP2-OD-004362
Because many of the most severe brain diseases and injuries involve damage to or death of brain cells, cell based therapies to repair the brain are attractive. Traditionally, cellular therapy has been conceived to entail injections or transplants of exogenous cells into recipients, either within or adjacent to the insult, or systemically. However, endogenous stem cell niches have been characterized, both in animals and in humans, and may present a therapeutic reservoir for cellular therapy. Here I propose innovative methods for steering large numbers of endogenous neural progenitor cells to areas of experimental stroke in somatosensory cortex in rodents. The stroke model will be the endothelin-1 induced vasoconstriction model. Following the stroke, neural progenitor cells will be labeled with MRI contrast agent directly in vivo. Next, these endogenous stem cells will be chemically manipulated, in vivo, first enhancing stem cell proliferation, then directing the migration of neuroblasts to stroke sites. in vivo cell tracking will be performed using high resolution magnetic resonance imaging, allowing the monitoring of therapeutic progress both spatially and longitudinally. Imaging data will be correlated to immunohistochemistry. Functional magnetic resonance imaging will be used to investigate restoration of function in the stroke sites due to the experimental therapeutic regiment and will be compared to standard behavioral assessments. If successful, significant impact can be achieved on stem cell therapy by realizing the full potential of a relatively unexplored source of therapeutic stem cells, the endogenous stem cells. However, equally important will be the further development and refinement of MRI methods for detecting single cells, in vivo. It is clear that cell therapy in humans will be greatly aided by the use of non-invasive methods for monitoring cell position and fate. The magnetic resonance imaging methods developed here will facilitate and expedite eventual human clinical applications.
William M. ShihDana-Farber Cancer Institute
Project Title: NMR Structure Determination of Membrane Proteins Enabled by DNA Nanotubes
Grant ID: DP2-OD-004641
The slow rate of membrane-protein structure determination represents a significant bottleneck for both basic and applied bioscience discovery, thus a tremendous need exists for innovative methodological breakthroughs. We propose to revolutionize NMR structure determination of α-helical, polytopic membrane proteins, with specific focus on those from mitochondria, through the employment of DNA-nanostructure-based alignment media. Recently, we developed a detergent-resistant liquid crystal of six-helix-bundle DNA-nanotubes that shows great promise as a robust tool for weak alignment of membrane proteins. Weak alignment enables measurement of global angular restraints that can serve as the primary source of structural information in studies of α-helical membrane proteins, where a sufficient number of distance restraints can be impossible to obtain; thus the effective size limit can be raised from 15 kDa to over 40 kDa. Realizing the potential of this technology to make feasible the NMR structure determination of a wide range of membrane proteins will require the development of additional DNA-based alignment tools that improve compatibility with positively charged proteins and that enable measurement of additional structural restraints. Towards these two ends, we will build and characterize the alignment capabilities of novel DNA nanostructures that either are longer, are coated with polyethylene glycol, or have helical axes perpendicular to the long axis of the alignment particles. We also will apply our DNA nanotools towards the NMR structure determination of peripheral benzodiazepine receptor, a 18 kDa polytopic α-helical, polytopic membrane protein that is involved in the steroidogenesis-limiting import of cholesterol across the outer mitochondrial membrane. This opportunity to advance membrane-protein structural biology arises from recognition of the need for custom-shaped, detergent-resistant materials matched with the unique expertise of the PI and his laboratory to self-assemble large, arbitrary 3D shapes from DNA.
Amy Jo WagersJoslin Diabetes Center
Project Title: Aging and Rejuvenation of the Hematopoietic Stem Cell Niche
Grant ID: DP2-OD-004345
Aging typically involves progressive decline in the body’s ability to maintain homeostatic cell replacement and to regenerate tissues and organs after injury. Age-associated defects in the hematopoietic (blood-forming) system cause characteristic deficiencies in lymphocyte production, over-proliferation of hematopoietic stem cells (HSCs), and excessive myeloid cell production, which together lead to reduced immune function and frequent hematopoietic malignancies in elderly populations. How aging causes deterioration of hematopoietic function is still unclear, but our data strongly suggest that loss or functional impairment of HSCs is a critical component of this process. Our work further suggests that the effects of aging on HSCs arise largely from alterations in the aged environment that act to suppress HSC activity in older animals and can be reversed by factors that circulate naturally in the bloodstream. Thus, a primary focus of my laboratory, and central goal of this proposal, is to identify age-regulated pathways that can be manipulated to restore appropriate HSC number and function in aged individuals. My approach will exploit my laboratory’s unique capacity to identify and isolate both HSC and HSC-supportive bone-lineage “niche” cells, in conjunction with our novel in vivo and in vitro models for assaying the influence of systemic factors on stem cell and niche cell function. Together, our studies will: (1) identify mechanisms of hematopoietic stem cell aging and rejuvenation, (2) determine the relationship between stem cell rejuvenating activity and longevity, and (3) reveal signaling pathways that may be useful for halting or reversing acquired HSC dysfunction during aging. Our findings ultimately may uncover conserved mechanisms of stem cell maintenance that are perturbed in old age and contribute globally to acquired deficits in tissue function. Application of these findings ultimately may help to delay or reverse the detrimental effects of aging, thereby extending the healthful life of aging individuals.
Jue D. WangBaylor College of Medicine
Project Title: The Molecular Interface of Replication Elongation and the Cellular Environment
Grant ID: DP2-OD-004433
Accurate DNA replication is essential for the survival and fitness of all organisms. Replication is believed to be regulated mostly during initiation. The central hypothesis of this proposal is that there also exist extensive regulatory mechanisms that control DNA replication even after initiation and possibly throughout elongation. My recent discovery of a novel regulatory mechanism of replication elongation by a small molecule established a precedent for such mechanisms. I plan to greatly expand this theme to include a spectrum of other small molecules and protein regulators. I propose that these regulators form a multifaceted interface between replication and other cellular processes. Through this interface, replication elongation can respond readily to metabolic and external cues; conversely, cells can monitor the replication status and respond accordingly. I have developed novel genomic tools to monitor aspects of replication in vivo that could not be observed before. Using these tools, I will define the nature of changes in replication elongation status under different conditions and study how it affects the choice of the cellular responses. I will then use metabolic and replication profiling to test the hypothesis that multiple small molecules induced by a spectrum of stresses regulate replication elongation robustly. Finally, using proteomic approaches, I plan to find protein factors that couple replication with other cellular processes, and examine their roles in regulating elongation and detecting replication stress. These studies will be carried out in model bacteria but will be extended to higher organisms in the future. Our ultimate goal is to expand the existing paradigm of replication control to include extensive post-initiation regulatory mechanisms. The factors identified in our study are likely to play paramount roles in the maintenance of genome stability and prevention of genetic diseases and cancer.
Lei WangSalk Institute for Biological Studies
Project Title: Genetically Encoding Novel Amino Acids to Investigate Wnt Signaling in C. elegans
Grant ID: DP2-OD-004744
Wnt is a morphogen released from signaling cells to transduce signals to other cells over large distances. Wnt signaling is extensively involved in developmental processes, including cell polarity, fate specification, and organogenesis, and is conserved from Caenorhabditis elegans to humans. Aberrant Wnt signaling has been implicated in many types of cancers. Wnt proteins and receptors are promiscuous in binding, and each of the coexisting multiple Wnt pathways elicits distinct cell responses. Conventional methods are ineffective in studying Wnt signaling due to the functional redundancy of Wnt signaling members as well as the difficulty in working with the small and heavily modified Wnt protein in vitro. Despite intense efforts, the mechanisms of Wnt secretion, gradient formation, and Wnt signal specificity are poorly understood. We propose to genetically encode unnatural amino acids (UAAs) into proteins in C. elegans, and to tailor UAAs with novel chemical and physical properties for new and precise studies of the Wnt signaling pathway directly in vivo. Fluorescent UAAs will be encoded to image the localization and trafficking of Wnt proteins, which cannot be tagged by bulky fluorescent proteins. Photocrosslinking UAAs will be used to covalently lock interacting Wnt molecules in vivo with high sensitivity and specificity for identification. These strategies will enable us to visualize Wnt export and trafficking in vivo, to untangle the multiple Wnt pathways, and to identify novel ligands or receptors. This study represents the first attempt to genetically encode UAAs in a multicellular organism. The success of this approach will provide a new set of methodologies with the potential to revolutionize the investigation of various biological and biomedical problems directly in vivo. New insights into the functions of Wnt secretion and receptor activation may help identify and ameliorate Wnt-related pathologies as well as implicate this machinery in other known diseases.
Joseph C. WuStanford University
Project Title: Inducing Pluripotency with miRNAs: New Paradigm Shift in Cell Reprogramming
Grant ID: DP2-OD-004437
Reprogramming of adult human fibroblasts into induced pluripotent stem (iPS) cells has generated significant excitement in the fields of regenerative medicine and stem cell biology. iPS cells avoid the ethical issues surrounding human embryonic stem cells (hESCs), and also have the potential for being patient- and disease-specific. However, the current method of integrating transcription factor genes into the adult cell genome requires weeks of cell culture, and so far has resulted in very low yields of iPS cells that may also become oncogenic in vivo. Inefficient delivery of transcription factors to the cells is an obstacle, but more fundamental is the failure of the introduced transcription factors to alter the pre-existing messenger RNA (mRNA) pool already within the adult cell. Thus, the adult cell’s existing transcriptome continues to be translated into adult proteins while the transcription factor mRNAs slowly reached target critical mass before overtaking the adult proteome, thus resulting in delayed pluripotency. To address these problems, I propose an innovative method for reprogramming that is based on microRNAs (miRNAs). MiRNAs are a class of small, noncoding RNA that play important posttranscriptional regulatory roles by targeting mRNA for cleavage or translational repression. The primary advantage of miRNA is that, unlike transcription factors, they will directly and immediately alter the adult transcriptome and proteome, leading to increased efficiency and decreased time for inducing pluripotency. I propose to do this by first determining the miRNA signature of adult cells after introduction of three known reprogramming factors, Oct 3/4, Sox2, and Klf4. Over-expression of this miRNA signature in adult cells using a novel non-viral delivery method should induce pluripotency. Further refinement with a microfluidic cell culture chip will define the critical individual miRNA(s) required for reprogramming. This creative approach posits an entirely new paradigm for iPS cell generation, and will help elucidate the molecular processes that underlie pluripotency and reprogramming.
Sean M. WuMassachusetts General Hospital
Project Title: Generation of Functional Organs Via Developmental Chimerism
Grant ID: DP2-OD-004411
Cell-based regenerative therapy holds tremendous promise to alleviate, if not cure, degenerative diseases such as diabetes, heart failure, and Parkinson’s disease. The availability of human pluripotent cells such as embryonic stem (ES) cells or the recently described induced pluripotent stem (iPS) cells have raised the prospect that differentiated progenies from these cells may be purified and transplanted in a clinical setting. Recent preclinical studies using cardiomyocytes derived from in vitro differentiated ES cells to regenerated damaged heart muscle have revealed significant difficulty in engraftment, expansion, and functional integration of the transplanted cells. These challenges are being addressed in different ways including tissue-engineering approaches; however, recapitulation of native tissue architecture may be extremely difficult given the variety of cell types involved. One possibility that these challenges may be overcome is if replacement tissue or the entire organ can be generated via normal developmental mechanisms in non-human species. This would ensure proper cellular architecture, vascularity, and most importantly, function. Cross-specie immune tolerance during embryonic development is a biological feature that has been well described in the literature. Little work has been done to show the developmental potential or limitations when pluripotent cells derived from one specie (e.g. rat or pig) are transferred into the developing blastocyst of another specie (e.g. mice or sheep), a procedure that has generated hundreds of genetically targeted mice thus far. Developmental compatibility is expected to correlate with the relatedness between species, but the extent of cross-specie tolerance is largely unknown. By exploring the developmental potential of interspecie chimerism, one may be able to assess, in the future, the feasibility of deriving replacement tissues using pluripotent stem cell such as iPS cells from human into genetically engineered non-human primates or large animals. Having an accessible supply of animal derived, genetically matched, human tissue for transplantation would truly herald the dawning of the era of regenerative medicine.
Julia ZeitlingerStowers Institute for Medical Research
Project Title: Investigating Developmental Potential Based on Genome-Wide Chromatin Status
Grant ID: DP2-OD-004561
While the epigenetic state of chromatin is thought to play an important role in regulating and maintaining gene expression programs during development, the general principles by which this occurs are only beginning to emerge. Recent advances in quantitative genomic approaches such as ChIP-chip and ChIP-seq provide a unique opportunity to elucidate the general rules by which chromatin states accompany and regulate developmental programs in vivo. However, generating sufficient high quality data to elucidate these rules is still challenging in mammalian systems because of the cell-type heterogeneity of embryos and the large amounts of cells required with current techniques. The goal of this proposal is to use genomic approaches to investigate the role of chromatin status during the development of Drosophila. Specifically, we are interested in identifying chromatin states that can predict which genes are likely to be activated in future gene expression programs and thus reflect the developmental potential of a cell. We have previously demonstrated the value of such approach by establishing ChIP-chip in Drosophila and by identifying stalled RNA polymerase II as a hallmark of developmental genes that are poised for activation. Here we test more generally the predictive value of stalled RNA polymerase II and chromatin states implicated in determining developmental potential, cellular memory and the response to signaling. Chromatin states to be tested include Polycomb group protein occupancy, specific histone modifications, nucleosome density and core promoter elements. All chromatin states will be analyzed across a developmental time-course and across specific cell lineages, both singly and in combination. Follow-up experiments with traditional Drosophila genetics will be used to test emerging hypotheses. Because chromatin states in Drosophila are likely to have similar predictive value in mammalian cells, this study will provide an important framework for understanding and predicting the development of normal and diseased cells in humans.
Kjersti M. Aagaard-TilleryBaylor College of Medicine
Project Title: Characterization of the Fetal Primate Epigenome and Metabolome Under In Utero Conditions of Maternal Obesity
Grant ID: DP2-OD-001500
Obesity causes substantial social, economic and health burdens. The rate of obesity is escalating disproportionately in children (infants to young adults). This rapid increase is unlikely to be due to environment or genetics alone. Accumulating evidence from our laboratory and others suggests that adult metabolic diseases originate in utero, and likely occur through the reprogramming of gene expression via epigenetic changes in chromatin structure (an altered "histone code"). Of interest, we have observed in a rodent transgenerational model of intrauterine growth restriction (IUGR) that a diet supplemented with essential nutrients, yet unaltered in its caloric content, prevents adult metabolic disease and is associated with abrogation of reprogrammed gene expression. However, although such established models in rodents demonstrate that fetal alterations in the histone code are involved in the persistence and conveyance of the altered postnatal phenotype, little is known about the effects of maternal diet and resultant obesity on primate fetal biology. We hypothesized that a high fat diet in non-human primates would induce changes in hepatic chromatin structure resulting in altered expression of fetal genes critical to the development of childhood and adult obesity. Based on our preliminary data, the focus of this proposal is to apply developed high throughput technology (comparative epigenomics and metabolomics) to decipher the primate epigenome and metabolome in the obese maternal environment and then measure the impact of supplementation on the differentially altered epigenome and resultant disease. The novel innovation and significance resides within its potential to provide (1) an expanded understanding of the mechanism through which a maternal high fat diet reprograms primate gene expression and (2) a simple intervention (essential nutrient supplementation with neither diet nor behavioral modification) with tremendous potential impact given the current obesity epidemic and the lack of efficacious therapeutics.
Ryan C. BaileyUniversity of Illinois Urbana-Champaign
Project Title: Personalized Clinical Diagnostics and Beyond: Integrated Ring Resonator Arrays
Grant ID: DP2-OD-002190
Paradigm shifts in biology are often catalyzed by innovations in measurement technologies. Genomics and proteomics have revolutionized biology but would not have been possible without developments in capillary sequencing, cDNA microarrays, and mass spectrometry, amongst other enabling technologies. Cancer biology has significantly benefited from the molecular-level detail provided by these tools, allowing elucidation of many perturbations underlying disease onset and progression. Unfortunately, many of the same measurement approaches are not applicable in the clinical setting and thus physicians do not have access to the same detailed biochemical information enjoyed by the academician. As a result, despite our increased knowledge of the molecular bases of cancer, the translation to clinical medicine has lagged significantly behind. This proposal describes a revolutionary biological analysis technology which has the potential to profoundly change the face of clinical medicine and beyond. High density arrays of extraordinarily sensitive integrated microring resonators will allow many gene and protein signatures to be simultaneously quantitated from a single patient sample. Distinguishing features of this technology include: sensitivity allowing PCR-less gene and single protein detection, label-free and real time operation, ultra-high scalability (>50,000 sensors/cm2), automated microfluidic operation, and commercially validated manufacturability via CMOS-compatible processing. To demonstrate the power of this technology, we will generate a molecular disease fingerprint allowing differentiation between three clinically indistinguishable yet biochemically distinct disease pathways underlying the deadly brain cancer glioblastoma multiforme. Importantly, each of these pathways is known to respond effectively to different therapeutic agents, thus personalized diagnosis equates to personalized treatment. We will also utilize this enabling technology to provide insight into profound questions surrounding post-transcriptional gene regulation and heterogeneity within the secreted responses of individual immune cells. This technology promises to broadly impact the landscape of the biomedical sciences, both meeting the clinical diagnostic challenges of today and pioneering the paradigm-shifting discoveries of tomorrow.
Edward S. BoydenMassachusetts Institute of Technology
Project Title: Novel Tools and Principles for Precisely Controlling Brain Activity
Grant ID: DP2-OD-002002
The finding that many neurological and psychiatric disorders are associated with abnormal neural activity in specific brain circuits raises the optimism that a precise, flexible technology for controlling neural activity would enable the systematic treatment of many brain disorders. I here propose to take a top-down approach to developing a new tool for noninvasive, focal, deep-targetable control of brain circuits. I also propose to discover informed principles governing the use of these tools to control activity in a diversity of neural circuits relevant for different illnesses. Through far-reaching collaborations, I will not only invent these tools and discover how to use them, but lead their translation into clinical application. I believe that this is the right time and place to tackle this intellectual challenge, given my unique training, as well as my proven abilities to synthesize new insights from disparate fields, and to lead interdisciplinary teams into new territory.
Frances A. ChampagneColumbia University, New York Morningside
Project Title: Epigenetic Mechanisms Mediating the Inheritance of Reproductive Behavior
Grant ID: DP2-OD-001674
Natural variations in mother-infant interaction have profound effects on offspring development and behavior. In particular, there is evidence for the influence of postpartum care on maternal behavior itself, such that low levels of maternal care are exhibited by females who received less care in infancy. This transmission of maternal behavior from mother to daughter has been previously associated with epigenetic regulation of estrogen receptor (ER) α in hypothalamic brain regions. The purpose of the proposed project is to explore these epigenetic effects in the context of reproductive behavior and develop convergent sources of evidence for the transgenerational influence of maternal care. To achieve this goal, the maternal regulation of social, sexual and maternal behavior will be explored in a rodent model. This will provide an experimental design for determining potential shifts in reproductive strategy in response to early environmental experiences. The reversibility of these maternal effects will be explored through pharmacological manipulation of DNA methylation within the promoter region of the ERα gene. The role of DNA methylation in the generational transmission of environmental experiences that occur beyond the postpartum period will also be investigated in response to gestational stress and juvenile exposure to differential levels of social interaction. Finally, ecologically valid paradigms will be developed in which transgenerational effects on reproductive behavior can be determined in a mouse model. These paradigms will involve 1) comparison of communally vs. non-communally reared offspring and grand-offspring, 2) caloric food restriction during lactation and 3) comparison of offspring born to either inexperienced or experienced mothers. Overall, this project will provide an innovative approach to both the study of inheritance and the role of epigenetic mechanisms in sustaining environmental effects within and across generations. Moreover, it will provide an experimental design for elucidating the occurrence of reproductive trade-offs in mammals.
Sean S. DaviesVanderbilt University
Project Title: Transformed Probiotic Bacteria for Treatment of Chronic Diseases
Grant ID: DP2-OD-003137
The continual increase in the number of patients suffering from chronic medical conditions that require long term treatment with therapeutic drugs such as hypercholesterolemia, hypertension, diabetes, and obesity has proven a tremendous economic burden, both to individuals and to health care systems. The traditional approach to drug production has been chemical synthesis of the needed compounds, then purification, formulation, and distribution. We propose to investigate a novel approach to long-term drug production and delivery: using probiotic intestinal bacteria transformed to express the required drug and inoculated into a patient for chronic colonization and therapeutic production. This approach essentially takes the notion of gene therapy and rather than altering the genomic DNA of the patient, instead alters the DNA of the patient's commensal bacteria, a far more tractable system. Probiotic intestinal bacteria such as members of the Lactobacillus family are routinely added to foods such as dairy products, have essentially no pathology, and can be readily transformed with exogenous DNA. Lactobacillus transformed with therapeutic proteins and peptides or sets of enzymes to synthesize specific drugs may therefore represent a versatile platform for sustainable therapy. We will determine the optimal strains of Lactobacillus for expression in mice as a model organism and perform additional engineering of the strain as necessary to ensure persistence in the intestinal tract and regulated expression of peptide or proteins. We will also develop methods for rapidly depleting the transformed bacteria without damaging other commensal bacteria, as a safety precaution against the advent of any unexpected adverse responses during the use of these therapeutically transformed bacteria. We will then examine the effect on atherosclerosis-prone mice of expressing peptides with known therapeutic actions. Our final aim will be to test the feasibility of producing small molecule drugs such as lovastatin in vivo by transforming the bacteria with the required synthetic enzymes.
Pedro Fernandez-FunezUniversity of Florida
Project Title: Mechanisms of Prion Misfolding
Grant ID: DP2-OD-002721
Prion diseases are a group of aggressive, lethal and incurable neurodegenerative disorders. The hallmark pathological event in these maladies is the misfolding, aggregation and brain deposition of “scrapie” Prion protein (PrPSc), which leads to spongiform degeneration of brain neurons. Unfortunately, a major gap exists in our understanding of how the conformational conversion of PrP ultimately kills neurons. Recent in vitro studies suggest that molecular chaperones may be key factors mediating PrP conversion and neuronal dysfunction. However, the functional relevance of this finding is unknown. My central hypothesis is that targeted expression of molecular chaperones can suppress PrP misfolding and PrP-mediated neurodegeneration. To that end, I created a novel and powerful Drosophila model of sporadic prion disease in which wild type PrP from Hamster converts into PrPSc–like conformations and causes spongiform degeneration. Supporting my hypothesis, human Hsp70 prevents PrP misfolding and protects against PrP-dependent neurotoxicity in transgenic flies. The overall goal of this project is to define the role of molecular chaperones in PrP misfolding by a multidisciplinary approach that combines the power of Drosophila genetics with mammalian cellular systems and mice. My specific aims are: 1) Genetic, biochemical and pharmacological approaches to study Hsp70 protection against PrP misfolding and neurotoxicity in Drosophila; 2) Determination of the ability of the Unfolded Protein Response components XBP1s and Grp58 to suppress PrP misfolding and neurotoxicity in Drosophila; 3) Role of molecular chaperones in prion replication in simplified mammalian systems, and 4) Potential therapeutic role of Hsp70 in mouse models of prion diseases. I anticipate that our studies will contribute to better understand the molecular basis underlying PrP conversion. In addition, by exploring the role of chaperone-inducing compounds in flies and mice, I may discover effective and innovative therapeutic interventions for treating these devastating and yet incurable diseases.
Sarah M. FortuneHarvard University (School of Public Health)
Project Title: Variation in M. tuberculosis in Response to Host Selection
Grant ID: DP2-OD-001378
All pathogens that cause chronic infections must avoid clearance by the host immune response. Many have complex mechanisms to rapidly generate diversity in critical antigens. Mycobacterium tuberculosis chronically infects one third of the worlds' population and similarly must avoid clearance by the host immune system. However, there is currently little understanding of whether M. tuberculosis, like so many other pathogens, diversifies in vivo to escape host immune selection. In this proposal, we will test the hypothesis that M. tuberculosis varies, either genetically or epigenetically, during the course of infection and that this variation contributes to the ability of the bacteria to avoid clearance by the host immune response. We will use new genomics technologies—low cost genome sequencing and expression profiling—to systematically assess genetic and epigenetic variation in bacteria selected in a simple experimental model of disease chosen to create different immune pressures on the bacteria —mice of different MHC haplotypes. In these studies, we expect to provide fundamental insights into the mechanisms and targets of diversifying immune selection in M. tuberculosis.
Levi Alexander GarrawayDana-Farber Cancer Institute
Project Title: Defining Melanoma Therapeutic Avenues by Integrative Functional Genomics
Grant ID: DP2-OD-002750
Although tumor classification and patient stratification based on genomic criteria offers tremendous clinical potential, discerning critical effectors of tumor genetic alterations—and developing robust therapeutic avenues to intercept them—represents a formidable obstacle to translational oncology. Recent advances in large-scale ‘perturbagen' approaches (e.g., viral RNAi and small molecule screening) hold great promise to alleviate such bottlenecks; however, their systematic application in cancer biology would benefit markedly from robust in vitro cancer models that fully encompass the genomic diversity manifest in patients. Malignant melanoma offers a rich avenue in this regard: unlike other solid tumors, cells from this lethal malignancy are readily cultured in vitro, thereby providing a diverse and tractable system for genomic and functional studies. Accordingly, we propose to apply pooled RNAi and small molecule microarray screening sequentially to a panel of genetically characterized and patient-derived melanoma cell lines. We will assemble a lentiviral library targeting all expressed genes located within the portion of the genome that is amplified in melanoma, and perform pooled RNAi screening across a panel of 20 melanoma lines representative of the most prevalent melanoma genomic alterations. ‘Hits' (e.g., selectively depleted shRNAs) will be correlated with genomic patterns to identify (onco)gene targets of melanoma amplifications. We will validate the most promising target genes using a series of cell survival assays in vitro (in arrayed RNAi format) and tumor formation assays in vivo (using shRNA ‘mini-pools'). Finally, we will identify candidate ligands that bind the top target (onco)protein candidates by performing small-molecule microarray screens using epitope-tagged protein constructs. If successful, this project should elaborate a spectrum of target proteins and potential lead compounds linked to common genetic changes in melanoma. Moreover, these efforts should inform a “platformizable” integrated approach applicable to all cancers for which tractable in vitro models exist.
Tawanda GumboUniversity of Texas Southwestern Medical Center
Project Title: Efflux Pump Inhibitors to Reduce Duration of Antituberculosis Therapy
Grant ID: DP2-OD-001886
Tuberculosis has devastated mankind for millennia. Current therapy is based on a belief that Mycobacterium tuberculosis in lung cavities exists as one of three populations: rapidly growing bacilli in areas of high oxygen that are most effectively killed by isoniazid, slowly growing bacilli under acidic conditions that are killed by pyrazinamide, and non-replicating bacilli under low oxygen tension that are killed most effectively by rifampin. We and others have recently demonstrated that parts of this belief may be incorrect. In the current proposal, I provide evidence of a central role for drug-efflux pumps to each of the first line anti-tuberculosis drugs. These drug-efflux pumps may lead to high level resistance. However, even low-level resistance efflux pumps may still provide a crucial survival advantage that enables bacilli to survive antibiotic exposure. I propose that the differential induction of drug-efflux pumps under different microenvironmental conditions may be responsible for selective effect of first line antituberculosis compounds under different oxygen and pH conditions. Induction of these pumps leads to increased mutation rates and emergence of resistance in vitro and in vivo. Inhibition of the efflux pumps by a common inhibitor will lead to acceleration of M. tuberculosis microbial kill, whether the bacilli are replicating or not. Three inexpensive efflux pump inhibitors, which are currently commercially available off patent, will be utilized to test these hypotheses in vitro and in vivo. After that, preclinical pharmacokinetic-pharmacodynamic studies will be performed. The drug concentrations of the efflux pump inhibitors best able to shorten duration of standard antituberculosis therapy will then be identified. Using population pharmacokinetics and pharmacogenomics, these results will be translated via Monte-Carlo simulations to identify (a) optimal dose of inhibitor best able to achieve this in humans and (b) the optimal duration of this therapy in humans. These results will then be prospectively validated.
Nir HacohenMassachusetts General Hospital
Project Title: Revealing Pathogen-Sensing Pathways Using RNAi Libraries
Grant ID: DP2-OD-002230
The long-term goal of the proposed work is to apply a genome-wide lentiviral RNAi library that we have developed to dissect innate immune pathways in mammals. In this proposal, we describe a novel experimental strategy to explore an elaborate and ancient sensory system that detects pathogen-derived nucleic acids. The nucleic-acid sensory system has been implicated in the detection of most pathogens and in the initiation of two major autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis. Our two objectives are to identify a set of unknown DNA sensors and their pathways, and to understand how DNA and RNA sensors avoid being inappropriately activated by host DNA and RNA. To identify genes and proteins in the unknown DNA-sensing pathways, we will: (1) perform a rapid unbiased genome-wide pooled RNAi screen to identify the strongest hits; (2) apply a more sensitive arrayed RNAi screen to test the role of a pre-selected subgenome library of genes; (3) purify dsDNA-binding proteins and use mass spectrometry to identify these proteins; (4) characterize the functions of newly identified genes required for DNA-sensing. To explore the mechanisms that inhibit the sensing of self nucleic acids, we will: (1) perform a pooled RNAi screen to identify blockers of spontaneous activation in response to endogenous nucleic acids; (2) perform an arrayed screen to identify genes involved in detection of dying cell nucleic acids by dendritic cells. By understanding this detection system in depth, we will gain insight into the perpetual struggle between parasitic elements and their hosts, and the risks of autoimmunity in response to the host's own nucleic acids. In addition, the results of the studies will help in the rational development of vaccines using adjuvants that target nucleic acid sensors.
Ekaterina HeldweinTufts University Boston
Project Title: Structural and Mechanistic Studies of Herpesvirus Entry into Host Cells
Grant ID: DP2-OD-001996
Herpesviruses are human pathogens that infect their hosts for life, causing cold sores, genital herpes, blindness, encephalitis, cancers, and life-threatening conditions in immuno-compromised individuals. The goal of my research is to understand in atomic-level detail how herpesviruses enter host cells. Such information will be invaluable in designing anti-herpesvirus therapeutics to combat both viral infections and cell-cell spread. The herpesvirus cell-entry mechanism is very complex. Whereas other enveloped viruses use a single protein to effect cell entry, all herpesviruses require at least three proteins: gB, gH, and gL. These three proteins are thought to accomplish the fusion of viral and cell membranes – a pivotal step in viral entry – but their exact functions are obscure. I aim to determine how the gB and gH/gL proteins of Herpes Simplex Virus (HSV) work together to accomplish membrane fusion and how the signal from the receptor-binding protein, gD, triggers the membrane-fusion machinery. Uncovering how these proteins work in HSV infection will also reveal their functions in other herpesviruses because the membrane-fusion machinery, i.e., gB, gH, and gL, is highly conserved. My approach will combine the power of x-ray crystallography to determine the structures of individual proteins with the rigor of other biophysical and biochemical techniques to study their interactions. The outcome of this research will be a thoroughly determined and finely detailed picture of the herpesvirus-mediated fusion of the viral and cell membranes. Previous studies of virus-mediated membrane fusion in single-component systems have provided many crucial insights into the general mechanism of membrane fusion, involved in many normal cellular processes. But the complex multiprotein fusion machinery of herpesviruses is a better model for the regulated, multi-component cellular membrane fusion. Therefore, if we establish how herpesvirus glycoproteins interact to drive membrane fusion during cell entry, we will advance fundamentally our mechanistic understanding of membrane fusion.
Konrad HochedlingerMassachusetts General Hospital
Project Title: Reprogramming of Somatic Cells by Defined Factors
Grant ID: DP2-OD-003266
Nuclear reprogramming defines the dedifferentiation of adult cells into pluripotent embryonic cells and has enormous therapeutic potential as it allows generating genetically matched cells from patients for cell therapy. Reprogramming has so far been achieved by nuclear transfer into oocytes and by cell fusion between embryonic cells and somatic cells, two approaches that have serious technical or ethical limitations. Based on recently published observations, we have generated so-called induced pluripotent stem (iPS) cells directly from fibroblasts by retroviral overexpression of the transcription factors Oct4, Sox2, c-myc and Klf4. In contrast to the previously reported iPS cells, our iPS cells were indistinguishable from ES cells in their epigenetic state and developmental potential. Several crucial questions were raised by these findings; (i) what is the sequence of molecular changes that accompany nuclear reprogramming, (ii) what is the kinetics of reprogramming and does it require cell division, (iii) are different cell types at different differentiation stages equally amenable to reprogramming, and (iv) can human cells be reprogrammed into iPS cells? Resolving these questions will be critical for understanding the molecular nature of nuclear reprogramming and may lead to strategies that allow efficient reprogramming of patient's cells into pluripotent cells. The current limitations to solve these questions are the low efficiency of direct reprogramming and the inability to follow reprogramming in real time. We will tackle these questions by generating “reprogrammable mice” in which every single cell can be reversibly induced to express the four factors at levels necessary for reprogramming, and by attempting to reprogram human cells. The goals of this proposal are thus to determine (i) the robustness and kinetics of reprogramming, (ii) the hierarchy of transcriptional and epigenetic changes that accompany nuclear reprogramming, (iii) the responsiveness of different cell types to the four factors, and (iv) the feasibility of human reprogramming.
Kristen C. JacobsonUniversity of Chicago
Project Title: From Neighborhoods to Neurons and Beyond
Grant ID: DP2-OD-003021
The purpose of this three-phase study is to conduct a multidisciplinary-based investigation of the effects of individual, family, peer, and neighborhood characteristics on individual differences in adolescent problem behavior. Phase I consists of an in-school assessment of approximately 7,000 6th – 8th graders in 10 socioeconomically and racially and ethnically diverse schools in the Chicago Public School system. The purpose of Phase I is to obtain data on environmental and psychosocial factors that may account for socioeconomic and racial and ethnic differences in problem behavior. Phase II consists of a target sample of 400 full-, half- and unrelated sibling pairs drawn from the original Phase I study who, along with their primary caregivers, will be brought to the University of Chicago for detailed neuroscience and behavioral assessments. The primary purpose of Phase II is to identify the environmental, biological, and psychosocial variables that account for individual differences in problem behavior, and to further determine whether these effects are genetically or environmentally mediated. Phase III consists of an fMRI investigation using a target sample of 60 concordant and 40 extreme discordant sibling pairs drawn from the Phase II study. The primary purpose of Phase III is to identify the neurobiological substrates that account for within-pair differences in behavior, and to determine the extent to which nonshared environmental factors account for individual differences in neurobiological functioning. A small pilot study of 20 extremely discordant sibling pairs from Phase III will investigate whether environments alter gene expression via changes in DNA methylation. Because this nested design uses a bioecological framework to measure risk and protective factors at multiple levels of analysis- “from neighborhoods to neurons and beyond”- the resulting data uniquely allows for the investigation of mediating and moderating effects among environmental, psychosocial, biological, and genetic factors on individual differences in problem behavior.
Joanna L. JankowskyBaylor College of Medicine
Project Title: Selective Neuronal Silencing to Study Cognitive Decline in Alzheimer's Disease
Grant ID: DP2-OD-001734
Our understanding of neurodegenerative diseases is currently hindered by lack of a firm neurobiological link between the patient's symptoms and the underlying neuropathology. To advance, we must identify not only key biochemical changes, but also how these changes alter the function of specific circuits to cause neurological symptoms. I seek to understand how impairment of particular circuits initiates early symptoms of Alzheimer's disease (AD), and how addition of further dysfunction leads to the disease's ultimate decline. I will apply a new method of selective neuronal silencing in transgenic mice to examine the behavioral impact of inactivating neuronal circuits damaged in AD. My postdoctoral laboratory has developed a novel chloride channel that responds specifically to ivermectin by producing hyperpolarization that results in selective, reversible suppression of neuronal activity. I will use my expertise in transgenic technology to create a mouse in which the ivermectin channel is conditionally expressed under control of Cre recombinase. Mating this mouse to animals expressing Cre in selected neuronal populations will allow those cells to be silenced with systemic ivermectin. My goal is to explore the function of adult-born hippocampal neurons, as this population is severely diminished in mouse models for AD. I will examine the role of these cells in learning and memory by selectively silencing them at critical times in the acquisition, consolidation, and recall of new information. Additional studies will address the effect of silencing on the migration, morphology, and survival of these adult-born cells. My long-term plans are to examine the behavioral impact of silencing other circuits damaged later in the course of disease to understand how diminished activity in multiple domains results in the progressive cognitive decline of AD. In the process, I will generate a transgenic mouse for selective neuronal silencing that will be broadly useful to the neuroscience community.
Alan JasanoffMassachusetts Institute of Technology
Project Title: Genetically-Controlled MRI Contrast Agents for Functional Brain Imaging
Grant ID: DP2-OD-002114
Understanding how the brain controls behavior is one of the outstanding scientific problems of today. The methods most needed to study neural mechanisms of behavior will combine the noninvasiveness and whole-brain coverage of magnetic resonance imaging (MRI) with the precision of cellular recording techniques like electrophysiology and fluorescence microscopy. Here we propose to develop a new set of neuroimaging techniques that approach this ideal. The methods rely on the use of protein-based sensors that report aspects of neural function and may be targeted to specific cells or cell types. Unlike protein sensors developed previously for optical imaging, the sensors we propose to create will incorporate MRI contrast agents, meaning that they can be monitored across entire, intact brains; genetic targeting will allow neural activity of defined “circuit elements” to be identified and integrated into explanatory models of brain function. In the first two Specific Aims, we propose to form and apply genetically-encoded calcium-sensitive contrast agents based on the iron storage protein ferritin (Ft). Our preliminary data and recently published results indicate feasibility of the design, which we will test in rats once it has been validated in cell culture. Ftbased sensors may not offer enough sensitivity for functional imaging of sparse or subtle changes in neuronal physiology, however. To address this, we propose in Aims 3-4 to develop a second genetically controlled system in which markers of neuronal activity are transduced and amplified by enzymes into robust signals that may be read out using powerful exogenous contrast agents. This program is an ambitious and high-impact endeavor that, once accomplished, will change the way researchers study the brain. The PI and his laboratory have the diversity of experience, record of effective collaborations, and risk-taking spirit that will allow them to introduce a new generation of brain measurements and empirical approaches in neuroscience.
Mark D. JohnsonBrigham and Women's Hospital
Project Title: MicroRNA Biogenesis and the Cancer Proteome
Grant ID: DP2-OD-002319
Recent studies in human cancers have revealed defects in microRNA biogenesis that promote tumor aggressiveness and decrease survival via mechanisms that are poorly understood. Much of the control of protein expression by microRNAs occurs without alterations in mRNA expression, and single microRNAs may target dozens of mRNAs in a tissue specific manner. Thus, this broad-based decrease in microRNA synthesis presents a challenge to those trying to understand its downstream molecular effects on carcinogenesis. Here we propose a new strategy that will comprehensively identify the mechanisms by which defects in microRNA biogenesis decrease cancer survivorship. This approach involves the integration of genome-scale high throughput quantitative mass spectrometry analysis of the cancer proteome with genome-wide microRNA, mRNA and DNA analyses of human brain tumors (glioblastomas) that have intact or defective microRNA biogenesis. Novel algorithms that incorporate clinical variables will be used to generate an integrated genomescale view of identified differences, and clinically-related targets will be investigated further using in vivo and in vitro models. Preliminary studies in our laboratory using aCGH and mRNA microarrays revealed deletion at the DICER1 locus and decreased DICER1 mRNA expression in a subset of glioblastomas, and this correlated with decreased microRNA expression and survival. Genomewide analysis identified numerous microRNAs that were differentially expressed between glioblastomas with low versus high DICER1 expression. Cdk6, which promotes cell cycle progression, was a predicted target of several of these microRNAs. DICER1 knockdown in glioblastoma cells increased cell growth and upregulated Cdk6 protein expression. Importantly, Cdk6 protein was overexpressed in glioblastomas with low DICER1 expression, suggesting that Cdk6 upregulation may be one mechanism by which defective microRNA biogenesis contributes to increased tumor aggressiveness. This innovative and ambitious project will integrate mass spectrometry proteomics, genomics and clinical variables to comprehensively identify the mechanisms underlying the decreased cancer survivorship associated with dysregulated microRNA biogenesis.
Manuel LlinasPrinceton University
Project Title: Novel Antimalarial Strategies Using Metabolomic Network Discovery
Grant ID: DP2-OD-001315
Malaria is a major global health issue affecting over half a billion people and resulting in 3-5 million deaths annually. This disease is caused by parasites of the genus Plasmodium with P. falciparum being the most lethal species. The host-pathogen relationship between Plasmodium and the host red blood cell is responsible for all clinical manifestations of the malaria disease and is a continuous 48-hour cycle that can be faithfully reproduced in the laboratory. Despite over a century of research on malaria, it continues to be a major health problem largely because drug-resistant parasites are on the rise, circumventing long-efficacious drug treatments. Thus, there is a renewed urgency to identify novel chemotherapeutics to treat this disease. This proposal aims to provide the first global analysis of the metabolic host-pathogen interactions for Plasmodium falciparum as a means to identify novel drug targets. The metabolic pathways encoded in any pathogen genome define the repertoire of chemical processes that it can autonomously regulate. All other metabolites must be taken up from the host cell or metabolized from precursors available through the host. Therefore, the host cell and pathogen are intimately linked through the reliance of the pathogen on the host for nutrients. The genome of P. falciparum suggests that this organism is biochemically unique: 60% of its genome encodes proteins never seen before in biology, and the remaining 40% contains very few of the fundamental metabolic genes found in almost all other eukaryotes. This indicates that the mechanism of interaction between Plasmodium and the host red blood cell may reveal novel metabolic enzymes that can provide new targets for pharmacological intervention. Using recently developed mass spectrometry techniques, we will quantitate metabolites in Plasmodium-infected cells and integrate these and other data to generate network interaction models revealing new biological insights into this deadly pathogen.
Feroz R. PapaUniversity of California San Francisco
Project Title: New Tools to Measure and Correct Endoplasmic Reticulum Stress in Single Living Cells
Grant ID: DP2-OD-001925
Aided by chaperones and other activities, proteins of the secretory pathway fold to their correct shapes in the endoplasmic reticulum (ER). But, if ER folding capacity is exceeded, unfolded proteins start to aggregate. This imbalanced condition—called ER stress—is being linked to diverse diseases, such as type 2 diabetes and cancer. The unfolded protein response (UPR) can rebalance a stressed ER, but if the stress is too great (or the response too weak), cells appear to cross a “tipping point”, and undergo apoptosis. This could explain why overworked insulin-producing pancreatic β-cells die in type 2 diabetes. On the other hand, a hyperactive UPR may allow malignant cells to survive hostile environments, promoting cancer. If we could measure both ER stress and the strength of corrective responses directly in healthy and diseased cells, we would be able to test these ideas quantitatively, and design rational therapies for these diseases. Structural engineers study system integrity by applying loads, measuring stresses, perturbing reinforcements, and making corrections. We propose similar approaches to ER stress disorders. Protein secretion generates and consumes oxidizing equivalents, so it should be possible to follow deviations in the ER's redox potential from its resting setpoint as an analog measure of ER stress. For this purpose, we are making redox-responsive fluorescent proteins to gauge the ER's redox potential in single, living cells. We have learned to stably perturb ER protein folding by converting an unfolded protein sensor called Ire1 into a finely adjustable rheostat. In living pancreatic β-cells, these tools will allow us to quantify the ER stress caused by insulin folding load, in both healthy and diabetic states. Finally, using a biochemical assay we have developed, we will discover molecules targeting Ire1, to increase or decrease ER folding ability, as appropriate corrective measures for various ER stress disorders.
Dana Pe'erColumbia University, New York Morningside
Project Title: Genetic Variation and Regulatory Networks: Mechanisms and Complexity
Grant ID: DP2-OD-002414
The focus of the proposed research is to understand the effect of sequence variation on the function of molecular networks. We will develop computational algorithms that integrate genotype, gene expression and phenotype data to construct models that describe how sequence variation perturbs the regulatory network, alters signal processing and is manifested in cellular phenotypes. Our approach is based on Bayesian networks, a framework we pioneered for the reconstruction of molecular networks from high-throughput data. We recently applied this framework to develop the Geronemo algorithm which we applied to yeast and uncovered a novel relationship between the sequence specific RNA factor PUF3 and P-Bodies, as well as a Single Nucleotide Polymorphism (SNP) in MKT1 that modulates this relationship. Both novel findings were experimentally validated subsequent to their discovery. Our approach is based on the complementary duality between genetic sequence and functional genomics. A significant influence of genotype on phenotype is induced by fine tuned perturbations to the complex regulatory network that governs a cell's activity. Variation in the expression of a single gene is more tractable and can be used as an intermediary to help associate genetic factors to the more complex downstream changes in phenotype in a hierarchical fashion. Conversely, DNA sequence polymorphisms are effective perturb-agens which provide a rich source of variation to help uncover regulatory relations in the molecular network as well as direct their causality. We will develop our methods using a large collection of highly variable yeast strains, for which we have generated robust quantitative growth curves under numerous environmental conditions. The methodologies piloted in yeast will be extended to genotype and gene expression data derived from tumor samples to attempt to elucidate the multiple genetic factors that drive their proliferation. These tools will be made publicly available, including a friendly graphical user interface and visualization.
Kathrin PlathUniversity of California Los Angeles
Project Title: Chromatin and Epigentic Inheritance
Grant ID: DP2-OD-001686
Covalent modifications of both DNA and histones are important for regulating gene expression. Here, I propose to address two fundamental, unanswered questions about chromatin modifications: i) how are changes in chromatin states established during development; and ii) once established, how are chromatin modifications stably preserved through future cell divisions? Initially, we will focus our analysis on understanding how the noncoding RNA Xist establishes silencing of the X chromosome in female mammalian cells. During initiation of X inactivation, Xist RNA spreads in cis to coat the X chromosome that will become inactive, mediates silencing, and triggers the sequential accumulation of chromatin modifications. How Xist RNA initiates silencing remains unknown. One approach to gain insight into the function of Xist is to identify interacting proteins. We have obtained results demonstrating that Xist is part of a large protein complex. In Aim 1, we therefore propose to use classical and nonconventional purification strategies to identify Xist -interacting proteins. To identify proteins necessary for maintaining the silence of the inactive X, we will perform an RNAi based screen in Aim 2, which is based on the reactivation of the inactive X. We expect to find proteins involved in the epigenetic inheritance of the silent X chromosome state. The cell cycle poses a particularly challenging problem for epigenetic inheritance since histone modifications have to be maintained when DNA strands are duplicated during S phase. A major question therefore is, how chromatin modifications are transmitted through cell divisions, and if they are indeed sufficient as carriers of the epigenetic information. Surprisingly, we have found that histone modifications on the inactive X do not accumulate throughout the cell cycle. In Aim 3, we will extend studies on the cell cycle regulation of histone modifications.
Michael P. RapeUniversity of California Berkeley
Project Title: Ubiquitin-Dependent Mechanisms of Tissue-Specific Cell Cycle Control
Grant ID: DP2-OD-003088
This proposal describes an integrated approach to identify modules of tissue-specific cell cycle control. Despite clear evidence for tissue-specificity in proliferation and the outstanding importance of tissue-specific cell cycle regulation for development and disease, the underlying mechanisms have not been uncovered. The identification and characterization of tissue-specific modules in proliferative networks will not only provide deep insight into development of multicellular organisms and tumorigenesis, but also lay the groundwork for the discovery of tissue-specific chemotherapeutics. Because of the crucial role of ubiquitination in cell cycle control, the tissue-specific expression of ubiquitination enzymes, the frequent misregulation of ubiquitination in cancer, and the enzymatic nature of ubiquitination, we will focus the dissection of tissue-specific cell cycle regulation on members of the ubiquitination machinery. Using synthetic lethality siRNA screens in different cell lines, we will identify ubiquitination enzymes required for tissue-specific cell cycle control. By isolating substrates of these enzymes unique to a certain tissue, we will delineate pathways underlying cell cycle regulation in this tissue. Finally, by developing and miniaturizing quantifiable ubiquitination assays, we will isolate small-molecule inhibitors that allow further dissection of proliferative networks and may serve as lead structures for novel tissue-specific chemotherapeutics. We are convinced that this integrated approach using genetic discovery, biochemical dissection, and inhibitor identification based on chemical biology will provide deep insights into cell cycle and developmental regulation and lay the groundwork for novel, innovative chemotherapeutics with improved tissue-specificity.
Jody Snow RosenblattUniversity of Utah
Project Title: Identification of Signals that Extrude an Apoptotic Cell from an Epithelium
Grant ID: DP2-OD-002056
I have discovered a mechanism called ‘extrusion', by which dying cells exit the epithelium without disrupting the barrier function of the layer. Here, a cell destined to die, signals its surrounding neighboring cells to form an intercellular actomyosin ring that contracts to squeeze the dying cell out. While stimuli that induce cell death (apoptosis) activate extrusion, we have also found that apoptosis and extrusion are not interdependent. This suggests that extrusion may remove cells from the epithelium in other circumstances. Signals that promote extrusion could, therefore, be used when cells leave the epithelium during developmental differentiation or initiation of tumor cell metastasis. Because most high-grade tumors have mutations in the apoptotic pathway, mutations that block apoptosis but not extrusion could enable a tumor cell to easily exit the epithelium and initiate its metastasis to other sites. Because metastasis is generally associated with cancer lethality, we believe that understanding the signalling that drives extrusion may be of utmost importance. We will also explore if extrusion might precede and induce apoptosis in overcrowded regions during normal homeostasis as a way of regulating cell numbers. Identifying the signals that trigger extrusion will be key to understanding the physiological functions that extrusion plays. We plan to identify the signalling pathway that initiates commitment of cell extrusion by investigating where this pathway bifurcates from the apoptotic pathway. We will also identify the downstream extra-cellular lipid signal that elicits extruding ring formation, as we think that this signal might provide a good molecular marker for extrusion. With these signals in hand, we will be able to test the function of extrusion in potential processes ranging from maintaining epithelial numbers and function to novel mechanisms for tumor formation and initiating tumor cell metastasis. To do so, we will extend our extrusion studies into whole zebrafish embryos.
Alan SaghatelianHarvard University
Project Title: Discovery Metabolite Profiling of the Prolyl Peptidases
Grant ID: DP2-OD-002374
Elucidation of the molecular mechanisms that underlie disease is crucial for the development of new therapeutic agents. Researchers have recently developed a number of methods to identify the genes, proteins, and metabolites associated with disease. However, complementary methods that define connections between these molecules—connections that are the foundation of biological models of disease and targeted medicine—have proven much more difficult to develop. As a result, there remains a tremendous need for innovative new approaches that reveal interactions between the molecular components of disease in vivo. The following proposal outlines the continued development and application of one such method, termed discovery metabolite profiling (DMP), for the assignment of endogenous substrates to the prolyl peptidase family of enzymes. DMP integrates an array of biological and chemical methods, including genetics, pharmacology, and analytical chemistry to identify bona fide physiological enzyme-substrate interactions. Importantly, by using DMP to study a family of enzymes that are virtually lacking in known endogenous substrates, but regulate phenotypes of tremendous biomedical interest, this research will begin to realize the incredible potential of the prolyl peptidases in medicine. Furthermore, the application of DMP to peptidases will demonstrate the generality of this approach for the future characterization of medically relevant enzymes and signaling pathways.
James ShorterUniversity of Pennsylvania
Project Title: Amyloid Elimination by Hsp104 and Substrate-Optimized Variants
Grant ID: DP2-OD-002177
We are in dire need of innovations to combat several increasingly prevalent and inexorably lethal neurodegenerative disorders, including Alzheimer's and Parkinson's disease, which voraciously devour our social and economic resources. These disorders share a common pathogenic mechanism in which specific proteins misfold into a shared surprisingly generic conformation, termed amyloid. Amyloid fibers of diverse proteins adopt a similar ‘cross-β' structure, in which the strands of the β-sheets run perpendicular to the fiber axis. Further, highly cytotoxic oligomers possessing a distinct generic structure frequently accumulate prior to fibers. Although the specific protein that forms amyloid and precise localization of the deposits varies in each disease, these shared facets of amyloidogenesis bring hope that therapeutic strategies that target amyloid may have broad applications. The exceptional stability of amyloids, however, including: protease- and SDS-resistance, makes them extraordinarily difficult to clear. Indeed, they are widely perceived as intractable. Remarkably, we have found that a proteinremodeling factor from yeast, Hsp104, can rapidly disassemble amyloid fibers and oligomers comprised of the yeast prion proteins, Sup35 and Ure2. The unprecedented alacrity at which Hsp104 remodels these amyloid structures raises awareness that amyloid conformers are not intractable, and that a cellular factor capable of reversing amyloidogenesis has evolved. Curiously, although highly conserved in plants, bacteria and fungi, Hsp104 has been mysteriously lost from metazoan lineages. We hypothesize that application of Hsp104 to disease-associated amyloids may have broad therapeutic potential. Hence, we aim to: (1) annihilate amyloid fibers, oligomers and associated proteotoxicity of diverse human disease-associated proteins using Hsp104; (2) engineer or evolve substrate-optimized Hsp104 variants that attack select amyloidogenic proteins; and (3) generate Hsp104 or substrate-optimized variant therapies for animal models of amyloid-disorders. These studies will provide the foundations for new approaches to attack the devastating amyloid-disorders that plague humankind.
Dorthy A. SipkinsUniversity of Chicago
Project Title: Stem Cell, Tumor and Bone Marrow Microenvironment Cross-Talk In Vivo
Grant ID: DP2-OD-002160
A growing body of evidence suggests that the host microenvironment plays an important role in the regulation of both normal and malignant stem cell self-renewal and differentiation. The specific locations, cellular components and molecular details of these stem cell niches are, however, little understood. Using in vivo confocal and multiphoton molecular imaging techniques to study cell interactions in the intact murine bone marrow (BM), we have defined a novel perivascular tumor and hematopoietic stem/progenitor cell (HSPC) niche. We have identified the molecules used by leukemic cells to access this niche, however the mechanisms governing HSC transit to these areas have not yet been defined. Moreover, the role of this niche in maintaining normal HSCs or coordinating specific HSC cell functions is unknown. Given the importance of HSC-based transplantation therapies as well as the clinical significance of tumor metastasis to the BM, there is great therapeutic potential in understanding these cellular interactions. The long-term goals of our research are, therefore, to define the molecular architecture and functional significance of this tumor and HSC niche using state-of-the-art in vivo imaging techniques combined with cell and molecular biology approaches. Specifically, we will 1) examine the mechanisms governing HSC transit and engraftment in these niches, 2) determine how tumor growth impacts the niche and whether tumor and benign HSCs compete within the niche, and 3) develop targeted nanoparticles to release encapsulated compounds in precise regions of the vascular niche. These nanoparticles will serve as a unique tool to elucidate the critical molecules that mediate HSC and tumor proliferation in the niche and as a prototype for a targeted drug delivery agent. Ultimately, we aim to use the knowledge from these studies to design specific anti-tumor treatments that spare normal hematopoiesis and to define factors that improve the efficacy of stem cell-based therapies.
David SpiegelYale University
Project Title: Small-Molecule Antibody Recruiting Therapeutics for Treating Human Disease
Grant ID: DP2-OD-002913
In recent years, antibody-based therapeutics have become important instruments in treating human diseases ranging from rheumatoid arthritis to cancer. However, these approaches suffer from certain limitations including severe (often fatal) side-effects, lack of oral bioavailability, and high cost. Here, we propose an alternative method that exploits the powerful cytolytic potential of antibodies already present in the human bloodstream. We will synthesize small-molecules capable of redirecting endogenous anti-2,4-dinitrophenyl (anti-DNP) antibodies to the surfaces of various pathogenic cell-types (Figure). As shown, bifunctional molecular constructs will be composed of a bivalent antibody-binding terminus (ABT), a cell surfacebinding terminus (CBT), and a linker region. Formation of a ternary complex between these agents, anti- DNP antibodies, and target cells, will lead to targeted cytotoxicity through various mechanisms including antibody-dependent cellular cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC). Applications of this approach to cancer and HIV treatment are described, along with more general directions. The proposed studies involve three aims: (1) to synthesize and evaluate an ABT capable of binding endogenous anti-DNP antibodies with high affinity, (2) to synthesize and evaluate a bifunctional small-molecule antiviral reagent targeting HIV gp120, and (3) to identify a small-molecule ligand for the interleukin-6 (IL-6) receptor for incorporation into bifunctional therapeutics targeting the B-cell malignancy multiple myeloma. Concise chemical syntheses of these agents are set forth, and encompass no more than six chemical transformations each. Biological evaluation will employ well established in vitro, and tissue culture models. Mathematical modeling studies are also reported that demonstrate numerically the feasibility of this approach for in vivo applications. Since high-throughput screening methods are ideally suited to identifying cell surface binding small-molecules, this general strategy is not limited to any particular type of target cell. If successful, the proposed method would represent a novel therapeutic approach to a variety of human diseases.
Eva M. SzigethyUniversity of Pittsburgh at Pittsburgh
Project Title: Understanding and Treating Neuropsychiatric Symptoms of Pediatric Physical Illness
Grant ID: DP2-OD-001210
Depression is costly and has detrimental effects on disease course in physically ill populations. This proposal takes a novel multi-dimensional approach to assess the neurobiological basis of depression in chronic pediatric physical illness using inflammatory bowel disease (IBD) as a model. It also evaluates the efficacy of a modified cognitive behavioral therapy (CBT) on emotional well-being, physical health, economic costs, and neurobiological outcomes. These results will provide key building blocks for a paradigm shift within medicine by integrating behavioral health into the comprehensive medical care of physical illnesses. Little is known about how the brain and body interact to increase depressive vulnerability, particularly during key developmental periods during childhood and adolescence. Adult studies identify disruptions in limbic and prefrontal brain activity in the pathophysiology of depression. Cytokines secondary to inflammation and exogenous treatment with steroids can cause mood and cognitive changes in these same brain regions. It is important to understand the neuropsychiatric effects of IBD and its treatment on underlying brain structures during adolescence, a critical developmental period for brain maturation underlying emotional regulation and cognitive processing. More importantly, neuronal plasticity during adolescence may still allow reversibility of disease-related brain effects through teaching coping strategies for life-long illness management that could change developmental trajectories and reduce vulnerability in adulthood. Using translational neuroscience approaches, this proposal will examine: 1) brain regions that underlie emotional and cognitive processing in youth with active IBD and depression using brain functional magnetic resonance imaging compared to youth with IBD and no depression, and normal controls; and 2) the efficacy of a combined CBT-physical illness narrative intervention targeting emotional and cognitive processing compared to supportive non-directive therapy at: (a) improving emotional well being; (b) alleviating physical symptoms; and (c) reducing health care costs.
Derek ToomreYale University
Project Title: Novel TIRF Microscopy for Analyzing Trafficking and Signaling at the Cell Cortex
Grant ID: DP2-OD-002980
My major goal is to advance knowledge about events on or near the plasma membrane. This region directly controls membrane traffic to and from the cell surface (exo- and endocytosis) and is where extracellular signals are amplified and modulated by assembly of signaling scaffolds. The introduction of total internal reflection fluorescence (TIRF) microscopy, a technique that allows unprecedented axial resolution, has revolutionized studies of dynamic processes at the cell cortex. I propose 1) to develop two highly innovative multi-angle TIRF microscopes and 2) to apply these instruments towards the elucidation of mechanisms that regulate exo- and endocytosis. These microscopes will allow the penetration depth of the light beam to be varied rapidly and avoid traditional imaging artifacts. Together with new analytical methods, they will permit high-resolution 3D imaging of a ~50- 1000 nanometer cortical region of living cells. Additionally, a highly innovative FRAP implementation will allow us to ‘pulse' photoactivate single vesicles and track their fate. I will use this novel instrumentation to expand our ongoing studies on exo- and endocytic traffic. A main new goal will be to elucidate mechanisms in the vesicular trafficking pathways that regulate levels of glucose transporters (Glut4) at the cell surface, a process whose dysfunction leads to type 2 diabetes. I will test the hypothesis that the exocyst complex participates in the spatial regulation of the insulin responsiveness of Glut4 vesicle exocytosis. Using photoactivatable Glut4-Dendra I will determine whether insulin signaling triggers a switch from lipid raft to clathrin-mediated endocytic pathways. To address where PI3K signaling acts, I will implement inducible dimerization technology to rapidly turn on/off PI(3,4,5)P3 at the plasma membrane. The innovative approaches of this proposal capitalize on my unique expertise in interdisciplinary research spanning instrumentation, cell biology, and quantitative biology and will fundamentally impact biology and a medically important field.
Jing YangUniversity of California San Diego
Project Title: Epithelial-Mesenchymal Transition in Tumor Metastasis
Grant ID: DP2-OD-002420
90% of cancer deaths are caused by metastatic growths in distant organs; however, the molecular basis of tumor metastasis is largely unknown. In a so-called “metastatic” primary tumor mass, only a small minority of carcinoma cells are actually migrating and on their route to disseminate into distant organs. To understand the cellular and molecular machineries that promote carcinoma cell dissemination, it is essential to identify and isolate such rare migrating carcinoma cells for molecular studies. A highly conserved developmental program Epithelial-Mesenchymal Transition (EMT) has been indicated in promoting metastasis progression. A group of embryonic EMT-inducing transcription factors, including Twist, Snail and Slug, are induced in carcinoma cells to promote cell motility and invasion. These transcription factors mainly function during embryogenesis, and they are mostly silent in normal adult tissues. Since activation of EMT is an early event to promote tumor cell dissemination, transcriptional activation of Twist, Snail and Slug provides a very specific and sensitive indicator of carcinoma cells that are undergoing EMT, migrating and disseminating into distant organs. In this study, I propose to use the promoters of Twist, Snail and Slug to drive the expression of a novel EMT detection/selection system, thus marking migrating tumor cells in vivo. Using this strategy, we aim to identify, image and isolate migrating carcinoma cells in primary tumors, to directly test the biological significance of EMT and cell migration in tumor metastasis in vivo, and to explore the signal pathways that promote carcinoma cells to migrate and disseminate into distant organs. If successful, our experiments will, for the first time, generate a molecular definition of the rare migrating carcinoma cells in vivo. The results from this study will not only significantly improve our molecular understanding of cancer metastasis, but also provide potential prognostic markers and specific targets for anti-metastasis therapies.
Mehmet F. YanikMassachusetts Institute of Technology
Project Title: Development of On-Chip Ultra High-Throughput Whole-Animal Assay Technologies
Grant ID: DP2-OD-002989
In recent years, the advantages of using the nematode Caenorhabditis elegans as a model system for human disease have become increasingly apparent, culminating in two Nobel Prizes in Physiology and Medicine within the last five years. Existing vertebrate animal models, and the instrumentation incorporated to study them, cannot be utilized for high throughput assays for rapid identification of novel genes, and drug leads. The model organism C. elegans allows in vivo genome-wide assays and high-throughput screens due to the availability of unmatched genetic techniques, its transparency, and the ability to grow it in minute volumes. Yet, since the first publications in early 1960s, little has changed how scientists manipulate this tiny organism manually, as a result of which even simple large-scale assays still take months to years to complete. Importantly, due to the lack of key technologies, several assays either cannot be performed at all or have to be dramatically simplified for high-throughput screens. We propose (1) development of the first on-chip ultra high-throughput whole-animal manipulation technologies for in vivo drug screens and genome-wide discovery of gene functions and interactions by complex on-chip behavioral and biochemical assay strategies; and (2) the first large-scale in vivo study of mechanisms of neural degeneration and regeneration following reproducible injuries using the proposed techniques. The proposed technologies and high-throughput assay strategies can significantly impact discovery of many molecular mechanisms using disease models of small animals.
This page last reviewed on August 10, 2017