Title of proposed idea: Exploring the Extracellular Space

Nominator: NIH Institutes/Centers

 Major obstacle/challenge to overcome: The Extracellular Space (ES) occupies the space between cells, outside their plasma membrane. The ES consists of the extracellular matrix (ECM) and the interstitial fluid.  It is filled with an ionic solution of mainly NaCl and contains a complex cocktail of molecules necessary for: 1) cellular survival (that includes glucose, amino acids, lipids, etc.), 2) tissue integrity (involving macromolecules such as collagen, lipoproteins, proteoglycans, glycoproteins, etc.), 3) physiological function of cells and tissues (such as growth factors, cytokines, hormones, neurotransmitters, metabolites, cholesterol, protease, protease inhibitors, etc.), and 4) transducing mechanical strain for proper tissue function. The volume, pH and composition of the ES can differ significantly between tissues and are altered dramatically upon pathological processes. Although there has been much focus in tools and technology development for the investigation of intracellular processes, proteins, and molecules, to date little attention has been devoted to the ES and how the cellular microenvironment contributes to health and disease.

Emerging scientific opportunity ripe for Common Fund investment:   Emerging tools and technologies already funded by the NIH Common Fund and other agencies that are being used to investigate and interrogate cellular processes will greatly accelerate understanding and control of the extracellular milieu in health and disease.  The convergence of the indicated fields below and the collaborative efforts of practitioners from these various disciplines will greatly advance our knowledge base of ES.

• Single cell analysis
• Glycomics
• Proteomics
• Metabolomics
• Glycopoteomics
• Lipidomics
• Molecular probes
• iPSCs generation and differentiation

NIH Common Fund investment would galvanize efforts towards a multidisciplinary approach towards determining the influence of the ES in health and disease.

Common Fund investment that could accelerate scientific progress in this field:  The NIH has some ongoing efforts in investigating the biology of extracellular space. The majority of these activities are focused on the role of ECM stiffness – a feature found in cancer and most diseases. A more synergistic approach catalyzed by Common Fund investments and utilizing cutting edge technologies as described above will provide a more global and comprehensive understanding of ES physiology and function and how these are perturbed in disease.  In addition, Common Fund investments will also provide impetus for the less appreciated information on the flow of gradients and soluble factors in tissue microenvironment. While we know of signaling of many growth factors and cytokines, we know very little how these molecules are organized in the ES space – after protease digestion for example, or during cell migration or morphogenesis. Moreover Common Fund investments will open up new areas of research on the exciting and novel roles of exosomes produced by cells of different origins.  Recent findings indicate that tumor cells (and likely various other cell types), much like immune cells, also secrete or produce exosomes which are loaded with miRNA and other RNA species, as well as constituted activated signaling molecules, such as AKT, which can through paracrine fashion modulate other cells.  There is some emerging evidence that the exosome cargo (e.g. miRNA) is actually released and picked by neighboring cells. Exosome-mediated transfer of mRNA and miRNA is a novel mechanism of genetic exchange. Moreover exosomal load assessment and exosomal molecular profiling, such as miRNA signatures, can serve as a source of diagnostic biomarkers that hold great promise for disease detection and monitoring.

Potential impact of Common Fund investment:  A thorough understanding of the cellular milieu can lead to breakthroughs in

• understanding and control of homeostasis
• intercellular communication
• paracrine and autocrine functions
• transport of nutrients, factors, metabolites, and degradation products to and from cells
• establishment of resting potential of cells
• tumor growth and metastasis
• neurodegeneration
• tissue injury and repair
• regenerative medicine
• drug delivery, since access of soluble drugs to cells in tissues is mediated by ES, and ECM macromolecules serve and can be exploited as attachment sites for various pharmacological compounds
• drug targeting and development
• biomarkers of disease
• cell re-programming
• cellular mimics of disease
• elucidating disease processes by bridging the gap between intracellular and extracellular events, and the crosstalk that takes place

Title of proposed idea: Developmental Origins of Health and Disease: Disease Prevention Across Generations

Nominator: NIH Institutes/Centers

Major obstacle/challenge to overcome: It is clear that many complex diseases and conditions result from a combination of genetics and environment.  What is not clear is when and how this interaction of genetics and environment actually leads to disease.  The concept of developmental origins of health and disease (DOHaD) is a fundamental principle underlying many chronic diseases and conditions in children and adults.  Decades of DOHaD studies suggest that a wide variety of early exposures occurring during periods of time where tissues and organ systems are developing markedly increase risk for (or even cause) disease across the life course.  These “environmental” exposures are varied and include drugs, nutrition, chemicals, stress, microbes or viral infections.  Examples of these non-communicable diseases and disorders (NCDs) include obesity, type II diabetes, insulin resistance, asthma, cardiovascular diseases, dyslipidemia, cognitive and  behavioral disorders, neurodegenerative diseases, a variety of cancers, and reproductive disorders.  Disadvantaged populations may experience greater exposure to these hazards and exhibit higher rates of disease incidence, morbidity and mortality.  Understanding and modulating this risk in humans during critical windows of development offers the promise of primary prevention for many of these NCDs and may result in reducing health disparities.  

Although the range of diseases and conditions believed to result (at least in part) from early life exposures spans nearly all of the NIH Institutes and Centers (ICs),  the concept of developmental origins has yet to be broadly adopted as a new research paradigm.   A trans-NIH program funded by the Common Fund (CF) will support research to 1) characterize early life exposures and their health effects in a comprehensive way, 2)  encourage cellular and molecular research on the mechanisms of these triggers (or stressors) on development, and 3) encourage the development of targeted interventional studies in human subjects.  The initiative would result in a new awareness among researchers funded across the NIH to consider the role of developmental stressors in triggering the diseases and conditions they study.  This would also jumpstart the field of transgenerational inheritance, i.e., the transmission of environmentally-induced phenotypes to subsequent generations without direct exposure.  This phenomenon is well-described in non-mammalian systems, but despite the existence of several published examples, it remains highly controversial whether it truly occurs in humans or rodents, or how common it might be.  Finally, the initiative would build the body of science needed to strengthen prevention research, an important element of health care reform.

Emerging scientific opportunity ripe for Common Fund investment:    No single IC has the capability or the expertise to integrate all the approaches and technologies needed to assess how genetics and multiple environmental triggers (or stressors) combine to affect health across the lifespan and even across generations. Furthermore, early life exposures even to a single stressor can lead to adverse health outcomes affecting multiple tissues and organ systems that are not readily appreciated in traditional single institute research programs.  For these reasons, adopting a coordinated, trans-NIH approach is a critical step in changing existing paradigms about the etiology of a variety of diseases and conditions, and transforming this information into knowledge that targets the most advantageous times, and possible interventions, to prevent their occurrence.  This program would also leverage and integrate current CF and trans-NIH initiatives such as those on epigenetics, exposure biology, genetics/genomics, the microbiome, bioinformatics, developmental biology and programming, stem cell development and differentiation, and animal, epidemiologic and clinical assessment of disease.

Common Fund investment that could accelerate scientific progress in this field:   We propose a CF program that will transform thinking about disease prevention: a comprehensive investigation of the developmental basis of a wide range of diseases and conditions.  Such a program would enable the NIH to identify a host of environmental stressors that increase disease risk, and the mechanisms by which these exposures alter normal developmental programs, manifesting in disease or conditions, years and even generations later.  Moreover, a comprehensive research program focused on the developmental origins of disease would enable scientists to pinpoint susceptibility windows – unique developmental time points at which humans are most susceptible to the combined effects of environmental exposures and genetic factors.  Identifying these developmental windows and developing predictive biomarkers of exposure will dramatically increase our ability not only to understand disease etiology, but also to develop intervention strategies that will ultimately prevent disease, by reducing exposure.  Possible investments include:

1.     Develop centralized, well-characterized, novel models and clinical research designs and analytic techniques that would promote effective multigenerational analysis and would leverage existing CF investments and infrastructure, such as that in mouse phenotyping (KOMP2).

2.     Identify stressors (nutritional, environmental, social) and investigate early gene-environment interactions that may perturb the normative development of various tissues and organ systems (such as the cardiovascular, neurological, immune, gastrointestinal, skeletal, endocrine, reproductive systems), increasing the risk of disease or conditions later in life and across generations.  Particular focus would be placed on diseases, conditions or syndromes that have been steadily increasing in incidence and where health disparities are apparent in the United States.  A focus on exposure characterization during early life would be imperative and would include vulnerable populations defined by race, ethnicity, and socioeconomic status.

3.     Apply state-of-the-art sequencing technologies to  investigate epigenetic and genetic mechanisms by which early life events lead to developmental reprogramming, impacting disease risk both in both children and adults (e.g., somatic or cognitive changes) long after the stressor is gone, and how increased risk is transmitted to subsequent generations through various mechanisms (i.e., germline, mitochondrial, or other changes).

4.     Use birth cohorts in human subjects, to identify sex-specific developmental susceptibility windows that are specific to common diseases and conditions in early development.  

5.     Identify biomarkers of developmental stress  for single exposures and combinations that predict susceptibility to specific diseases and conditions later in life that could also be used to target and develop preventive interventions.  

6.     Develop bioinformatics and statistical programs to allow the assessment and integration of developmental exposure to a variety of stresses and their importance in the development of disease outcomes.

Potential impact of Common Fund investment:  This would be the first CF program specifically designed to focus on disease prevention, and it will do it in an integrated and transformative manner.  Once it is clear how certain diseases or conditions originate in early development – including which stressors or combinations of stressors are responsible for the altered programming, and during which developmental stages humans are most sensitive to these effects – effective strategies can be developed both to reduce exposure to the stressors and or intervene to reduce disease incidence.  Such strategies have the potential not only to reduce the overall societal burden of disease but to reduce or eliminate health disparities.