R01ES036998

DISCOVERY OF GENE-BY-AIR POLLUTION INTERACTIONS IN RESPIRATORY DISEASE USING GENETICALLY DIVERSE MICE WITH VALIDATION IN HUMANS - PROJECT SUMMARY OUR GOAL IS TO IDENTIFY GENE-ENVIRONMENT INTERACTIONS (GXE) WITH ACUTE AND CHRONIC EXPOSURE TO THE AMBIENT AIR POLLUTANT OZONE (O3) THAT CONTRIBUTE TO COMMON, CHRONIC RESPIRATORY DISEASES LIKE ASTHMA AND COPD. HOWEVER, DETECTING GXE WITH O3 EXPOSURE IN HUMAN EPIDEMIOLOGIC STUDIES IS EXTREMELY CHALLENGING FOR A NUMBER OF REASONS, INCLUDING STATISTICAL POWER AND PRECISION OF EXPOSURE ASSESSMENT. TO OVERCOME THESE CHALLENGES, WE HAVE EXPLOITED GENETICALLY DIVERSE, MULTI-PARENTAL MOUSE POPULATIONS, NAMELY THE DIVERSITY OUTBRED (DO) AND COLLABORATIVE CROSS (CC, INBRED), AS GXE DISCOVERY PLATFORMS BECAUSE IN THESE MODELS WE CAN MAXIMIZE INFORMATION ABOUT BOTH GENETIC VARIATION AND O3 EXPOSURE. PREVIOUSLY, WE UTILIZED THE CC TO IDENTIFY A LARGE-EFFECT GXE QUANTITATIVE TRAIT LOCI (QTL) WITH ACUTE O3 ON CHROMOSOME (CHR) 15 THAT AFFECTED AIRWAY INJURY AND INFLAMMATION. AT THIS LOCUS, TWO CANDIDATE GENES EMERGED, ANGPT1 AND RSPO2. WE ALSO FOUND THAT A COMMON VARIANT AT THE ORTHOLOGOUS LOCUS IN HUMANS (RS10086579, LOCATED BETWEEN ANGPT1 AND RSPO2) AFFECTED RESPONSE TO ACUTE O3 IN HUMANS, DEMONSTRATING PROOF OF CONCEPT FOR OUR APPROACH. THIS VARIANT ALSO EXHIBITED GXE WITH CHRONIC AIR POLLUTION IN COPD, INDICATING IT LIKELY AFFECTS RESPONSE TO BOTH ACUTE AND CHRONIC EXPOSURE. HERE, WE PROPOSE TO FIRST IDENTIFY THE CAUSAL GENE ON CHR 15 IN MICE (ANGPT1 VS. RSPO2), THEN IDENTIFY NEW GXE QTL FOR BOTH ACUTE AND CHRONIC O3 RESPONSES. IN ALL CASES, WE WILL TRANSLATE OUR FINDINGS FROM MOUSE TO HUMAN THROUGH TARGETED ANALYSIS OF GXE WITH COMMON VARIANTS IN HUMAN ORTHOLOGS OF THE GENES WE IDENTIFY IN MICE USING EXISTING GENOTYPE AND O3 EXPOSURE DATA FROM 3 HUMAN STUDIES. THE HUMAN STUDIES INCLUDE (1) AN ACUTE O3 CHALLENGE DATASET (N=191) IN WHICH INFLAMMATION WAS QUANTIFIED, (2) THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS AIR POLLUTION STUDY (MESA-AIR, N~6000) IN WHICH ASSOCIATIONS BETWEEN CHRONIC O3 EXPOSURE AND COPD (EMPHYSEMA AND LUNG FUNCTION) HAVE BEEN QUANTIFIED, AND (3) THE CHILDREN’S HEALTH STUDY (CHS, N~1800) IN WHICH ASSOCIATIONS BETWEEN CHRONIC O3 AND CHILDHOOD-ONSET ASTHMA HAVE BEEN QUANTIFIED. IN AIM 1, WE WILL EVALUATE ANGPT1 AND RSPO2 USING KNOCKDOWN/KNOCKOUT AND RESCUE EXPERIMENTS IN MICE. IN PARALLEL, WE WILL CONDUCT AN EXPANDED HUMAN GENETIC ANALYSIS OF ACUTE AND CHRONIC O3 RESPONSE WITH RS10086579 AND NEARBY VARIANTS USING THE 3 HUMAN DATASETS. IN AIM 2, WE WILL IDENTIFY NEW GXE FOR ACUTE O3 RESPONSE IN MICE BY PERFORMING A QTL MAPPING STUDY INVOLVING TWO CC STRAINS THAT ARE PHENOTYPICALLY DIVERGENT BUT NOT DUE TO VARIATION AT THE CHR 15 QTL. GENE EXPRESSION QTL (EQTL) MAPPING IN ALVEOLAR MACROPHAGES (AM) AND MEDIATION ANALYSIS WILL BE USED TO IDENTIFY CANDIDATE GENES. WE WILL THEN TEST FOR GXE IN THE HUMAN STUDIES. IN AIM 3, WE WILL IDENTIFY GXE FOR CHRONIC O3 RESPONSE USING DO MICE, EMPLOYING A LONGITUDINAL STUDY DESIGN IN WHICH LUNG FUNCTION IS MEASURED PRIOR TO AND AFTER O3 EXPOSURE. AFTER MAPPING QTL AT HIGH RESOLUTION AND IDENTIFYING CANDIDATE GENES, WE WILL TEST FOR GXE IN THE CHS AND MESA-AIR. IN TOTAL, OUR WORK WILL REVEAL NOVEL GENES ASSOCIATED WITH THAT AFFECT O3-INDUCED ASTHMA AND COPD ONSET AND/OR PROGRESSION.

University Of North Carolina At Chapel Hill

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]

Chapel Hill, North Carolina 27599 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)