R01ES033625

Crispr Screens of Population Relevant Genes Governing Toxicant Resilience

People vary considerably in their response to and in the effects of exposure to chemical toxicants and biological toxins. As a result, the risk of adverse outcomes associated with exposure for different individuals and populations can be widely divergent. Gene by environment (G x E) interactions likely underlie a significant component of these risk differences. However, we remain largely ignorant of both the key genetic factors and the mechanistic association with specific toxins/toxicants. As a result, our capability to mitigate risk by the identification of susceptible individuals and populations to enable effective preventive efforts remains sorely limited.

Current approaches to identify G x E interactions rely on genetic association studies which generally lack sufficient power to identify significant associations, due to the large number of genetic variants and small populations of exposed individuals. We propose, in a fundamentally different approach, to first systematically identify the common human variants which impact the functional response to a specific toxicant/toxin to delineate key candidate G x E interactions for targeted consideration in relevant individuals and populations.

We will focus on functional interrogation of 1490 genes, the ToxVar set, which contain an aggregate frequency of loss of function mutations of >0.1% in all human populations assessed to date and previously identified as interacting with one or more toxicant/toxins. We contend that these commonly functionally compromised genes are most likely to impact human response to a toxin/toxicant in a significant proportion of people.

We will simultaneously query the impact of functional disruption in each of these 1490 genes on the cellular response to a toxicant using coupled Crispr screening and single cell toxicologically relevant gene expression targets (SCTRGETS). We will evaluate the ToxVar-SCTRGET approach to identify functionally relevant and commonly variant genes involved in cellular response to selected toxicants of high human relevance in increasingly physiologically relevant cell models.

University Of Florida

TO FOSTER UNDERSTANDING OF HUMAN HEALTH EFFECTS OF EXPOSURE TO ENVIRONMENTAL AGENTS IN THE HOPE THAT THESE STUDIES WILL LEAD TO: THE IDENTIFICATION OF AGENTS THAT POSE A HAZARD AND THREAT OF DISEASE, DISORDERS AND DEFECTS IN HUMANS, THE DEVELOPMENT OF EFFECTIVE PUBLIC HEALTH OR DISEASE PREVENTION STRATEGIES, THE OVERALL IMPROVEMENT OF HUMAN HEALTH EFFECTS DUE TO ENVIRONMENTAL AGENTS, THE DEVELOPMENT OF PRODUCTS AND TECHNOLOGIES DESIGNED TO BETTER STUDY OR AMELIORATE THE EFFECTS OF ENVIRONMENTAL AGENTS, AND THE SUCCESSFUL TRAINING OF RESEARCH SCIENTISTS IN ALL AREAS OF ENVIRONMENTAL HEALTH RESEARCH. SUPPORTED GRANT PROGRAMS FOCUS ON THE FOLLOWING AREAS: (1) UNDERSTANDING BIOLOGICAL RESPONSES TO ENVIRONMENTAL AGENTS BY DETERMINING HOW CHEMICAL AND PHYSICAL AGENTS CAUSE PATHOLOGICAL CHANGES IN MOLECULES, CELLS, TISSUES, AND ORGANS, AND BECOME MANIFESTED AS RESPIRATORY DISEASE, NEUROLOGICAL, BEHAVIORAL AND DEVELOPMENTAL ABNORMALITIES, CANCER, AND OTHER DISORDERS, (2) DETERMINING THE MECHANISMS OF TOXICITY OF UBIQUITOUS AGENTS LIKE METALS, NATURAL AND SYNTHETIC CHEMICALS, PESTICIDES, AND MATERIALS SUCH AS NANOPARTICLES, AND NATURAL TOXIC SUBSTANCES, AND THEIR EFFECTS OF ON VARIOUS HUMAN ORGAN SYSTEMS, ON METABOLISM, ON THE ENDOCRINE AND IMMUNE SYSTEMS, AND ON OTHER BIOLOGICAL FUNCTIONS, (3) DEVELOPING AND INTEGRATING SCIENTIFIC KNOWLEDGE ABOUT POTENTIALLY TOXIC AND HAZARDOUS CHEMICALS BY CONCENTRATING ON TOXICOLOGICAL RESEARCH, TESTING, TEST DEVELOPMENT, VALIDATION AND RISK ESTIMATION, (4) IDENTIFYING INTERACTIONS BETWEEN ENVIRONMENTAL STRESSORS AND GENETIC SUSCEPTIBILITY AND UNDERSTANDING BIOLOGIC MECHANISMS UNDERLYING THESE INTERACTIONS, INCLUDING THE STUDY OF ENVIRONMENTAL INFLUENCES ON EPIGENOMICS AND TRANSCRIPTIONAL REGULATION, (5) CONDUCTING ENVIRONMENTAL PUBLIC HEALTH RESEARCH, INCLUDING IN AREAS OF ENVIRONMENTAL JUSTICE AND HEALTH DISPARITIES, THAT REQUIRES COMMUNITIES AS ACTIVE PARTICIPANTS IN ALL STAGES OF RESEARCH, DISSEMINATION, AND EVALUATION TO ADVANCE BOTH THE SCIENCE AND THE DEVELOPMENT OF PRACTICAL MATERIALS FOR USE IN COMMUNITIES, WITH A FOCUS ON TRANSLATING RESEARCH FINDINGS INTO TOOLS, MATERIALS, AND RESOURCES THAT CAN BE USED TO PREVENT, REDUCE, OR ELIMINATE ADVERSE HEALTH OUTCOMES CAUSED BY ENVIRONMENTAL EXPOSURES, (6) EXPANDING AND IMPROVING THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (7) EXPANDING AND IMPROVING THE STTR PROGRAM TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (8) PROVIDING SUPPORT FOR BROADLY BASED MULTI-DISCIPLINARY RESEARCH AND TRAINING PROGRAMS IN ENVIRONMENTAL HEALTH .THESE PROGRAMS INCLUDE THE ENVIRONMENTAL HEALTH SCIENCES CORE CENTERS , WHICH SERVE AS NATIONAL FOCAL POINTS AND RESOURCES FOR RESEARCH AND MANPOWER DEVELOPMENT. THROUGH THESE PROGRAMS, NIEHS EXPECTS TO ACHIEVE THE LONG-RANGE GOAL OF DEVELOPING NEW CLINICAL AND PUBLIC HEALTH APPLICATIONS TO IMPROVE DISEASE PREVENTION, DIAGNOSIS, AND THERAPY. ADDITIONAL CENTERS PROGRAMS DEVELOPED IN RECENT YEARS, INCLUDE THE CENTERS FOR OCEANS AND HUMAN HEALTH (CO-FUNDED WITH NSF), CHILDREN'S ENVIRONMENTAL HEALTH CENTERS (CO-FUNDED WITH US EPA) AND THE AUTISM CENTERS OF EXCELLENCE (CO-FUNDED WITH OTHER NIH INSTITUTES), AND THE HUMAN HEALTH EXPOSURE ANALYSIS RESOURCE (HHEAR) PROGRAM, (9) SUPPORTING RESEARCH TRAINING PROGRAMS WHICH SERVE TO INCREASE THE POOL OF TRAINED RESEARCH MANPOWER WITH NEEDED EXPERTISE IN THE ENVIRONMENTAL HEALTH SCIENCES THROUGH SUPPORT OF INDIVIDUAL AND INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS), (10) THE OUTSTANDING NEW ENVIRONMENTAL SCIENTIST PROGRAM WHICH PROVIDES FIRST TIME RESEARCH GRANT FUNDING TO OUTSTANDING JUNIOR SCIENTISTS IN THE FORMATIVE STAGES OF THEIR CAREER WHO ARE PROPOSING TO MAKE A LONG TERM COMMITMENT TO ENVIRONMENTAL HEALTH SCIENCES RESEARCH AND TO ADDRESS THE ADVERSE EFFECTS ON ENVIRONMENTAL EXPOSURES ON HUMAN BIOLOGY, HUMAN PATHOPHYSIOLOGY AND HUMAN DISEASE.

93.113 - Environmental Health

National Institute of Environmental Health Sciences (NIEHS) [HHS - NIH]

Gainesville, Florida 326115500 United States

Single Zip Code

Utilizing In Vitro Functional Genomics Advances for Gene-Environment (G x E) Discovery and Validation (R01 Clinical Trial Not Allowed) (RFA-ES-20-018)

Amendment Since initial award the total obligations have increased 1278% from $250,000 to $3,445,316.