We Accelerate Discovery

Program Highlights

Spatial Recognition in Receptors

The tyrosine kinase AXL receptor plays an important role in blood clotting and immune regulation and is implicated in the drug resistance and spread of tumors. Despite the significant role of the AXL receptor, it is unknown how its ligand and other factors influence AXL activation. Meyer, a 2014 awardee, and colleagues sought to understand how the receptor senses interaction of its ligand, Gas6, with the lipid phosphatidylserine. Using quantitative experiments and mathematical modeling, Meyer and others show that AXL does not respond solely to concentrations of Gas6 but also to the spatial presentation of Gas6. This insight helps resolve AXL receptor function and will aid the design of future therapies to a wide range of cancers.

The AXL Receptor Is a Sensor of Ligand Spatial Heterogeneity. Meyer AS et al. Cell Systems. 2015 July 29; doi: 10.1016/j.cels.2015.06.002. Exit Disclaimer

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Silencing the X Chromosome

In addition to protein coding genes, the human genome also encodes thousands of functional long non-coding RNA (lncRNA) genes. How these lncRNAs control gene regulation is unknown, largely because of technical limitations in defining lncRNAs complexes in the cell. Scientists at Caltech developed a new approach allowing them to look at lncRNA complexes in cells. Using this approach, the researchers studied Xist, an lncRNA that is required for silencing an entire X chromosome during normal female development. They were able to identify the proteins that directly interact with the Xist RNA and, ultimately, are necessary to silence transcription of the X-chromosome. One of these interacting proteins, called SHARP, is required for excluding RNA Polymerase from genes across the X chromosome. The protein does this by recruiting a key chromatin regulatory protein called HDAC3, which acts to modify the structure of chromatin to silence transcription. These results provide the first detailed view of how a lncRNA controls gene regulation.

The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3. McHugh CA et al. Nature. 2015 April 27; doi:10.1038/nature14443.

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Are Gut Bacteria the Key to Treating Low Serotonin Levels?

There is an increasing appreciation that mammals have co-evolved with trillions of microorganisms, collectively called the “microbiota,” which regulate a variety of biological processes, including the development and function of the nervous system. New research explores fundamental interactions between gut microbiota and the mammalian host in regulating levels of neurotransmitters. In a study from the laboratory of 2013 Early Independence Awardee Elaine Y. Hsiao at the California Institute of Technology, they find a striking ~60% of peripheral serotonin is regulated by microbiota and identify bacteria from mice and humans that can regulate host serotonin production in the gut. When microbe-free mice are colonized with serotonin-promoting microbes, serotonin levels rise and can correct enteric and hemostatic abnormalities related to low levels of serotonin. The researchers further reveal particular microbial metabolites involved in serotonin regulation. These findings reveal a fundamental host-microbial interaction and raise the question of whether microbe-based treatments for symptoms and diseases caused by low levels of serotonin are possible.

Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Yano JM et al. Cell. 2015 April 9; 161:264-276.

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2013 Early Independence Awardee Demonstrates Neurological Dysfunction in Mouse Model of Kabuki Syndrome is Potentially Reversible and Linked to Adult Neurogenesis

Dr. Hans Tomas Bjornsson, MD, PhD, an assistant professor at the McKusick Nathans Institute of Genetic Medicine and the department of pediatrics at the Johns Hopkins University School of Medicine, has published a paper in the journal Science Translational Medicine, describing that a deficiency of dentate gyrus neurogenesis may underlie some of the neurological dysfunction seen in a mouse model of Kabuki syndrome, a rare Mendelian cause of intellectual disability. Using a drug known to target the epigenetic machinery, Bjornsson and his team demonstrated recovery of the neurogenesis defect in association with normalization of hippocampal memory defects in the treated mice. These findings suggest that Kabuki syndrome may be a treatable cause of intellectual disability even in postnatal life and raises the possibility whether deficiency of neurogenesis may underlie additional causes of intellectual disability.

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2012 Early Independence Awardee Receives Young Investigator Award For Schizophrenia Research

Dr. Alan Anticevic, Ph.D., was selected as one of the Young Investigator Awardees at the 14th International Congress on Schizophrenia Research (ICOSR). The ISCOR meeting is held biennially and is intended to encourage the gathering and exchange of data, techniques, and ideas from the schizophrenia research community. The Young Investigator Awards are given to bright young scientists producing high quality research related to the field of schizophrenia. Dr. Anticevic is a 2012 NIH Director’s Early Independence Awardee (EIA) whose EIA funded research is focused on understanding the underlying mechanisms of cognitive and affective disturbances in neuropsychiatric conditions, including schizophrenia, though an approach which combines neuroimaging, pharmacology, and computational modeling. The ultimate goal of his research is to be able to facilitate rationally-guided cognitive treatments for this devastating illness.

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Adam de la Zerda, Mitchell Guttman, Gregory Sonnenberg, Daniela Witten

Forbes Magazine Names 4 NIH Stars among the 2012 “30 under 30" in Science and Innovation

The NIH Director's Early Independence Award is a relatively new funding mechanism that provides an opportunity for exceptional junior scientists to "skip the post-doc," and start an independent research career at a supportive Institution directly following the completion of their graduate degree or clinical residency. For the second year in a row, Forbes Magazine has selected several NIH Director’s Early Independence Awardees for the honor of "30 under 30" in Science and Healthcare for 2012.

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Forbes Magazine Names 5 NIH Director's EIA Awardees
among Top Science and Innovation "30 under 30" for 2011John Calarco, Ph.D.James S. Fraser, Ph.D.Jeffrey M. Kidd, Ph.D.Harris H. Wang, Ph.DDaniela Witten, Ph.D

The NIH Director's Early Independence Award is a new funding mechanism that provides an opportunity for exceptional junior scientists to "skip the post-doc," and start an independent research career at a supportive Institution directly following the completion of their graduate degree or clinical residency. Five of the top honored "30 under 30" in Science and Innovation by Forbes Magazine are NIH Early Independence Awardees for 2011.

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