R01ES036210

RNA MODIFICATIONS IN APOLIPOPROTEIN REGULATION BY ENVIRONMENTAL EXPOSURES - EXPOSURE TO PERSISTENT ENVIRONMENTAL CONTAMINANTS INCLUDING POLYCHLORINATED BIPHENYLS (PCBS) CONTRIBUTES TO METABOLIC DISEASES INCLUDING METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD). ALTHOUGH PCB EXPOSURES ARE POSITIVELY ASSOCIATED WITH ALTERED LIVER ENZYMES, MIRNAS, MASLD, AND MORTALITY IN HUMAN COHORTS, HOW PCBS ACT IN COLLABORATION WITH A HIGH FAT DIET (HFD) TO PROMOTE INCREASED HEPATIC TRIGLYCERIDE ACCUMULATION, FIBROSIS, AND INFLAMMATION IN PROGRESSION TO METABOLIC-DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH) REMAINS UNKNOWN. FURTHER, ALTHOUGH LIVER SEXUAL DIMORPHISM AND SEX-SPECIFIC DIFFERENCES IN HUMAN HEALTH OUTCOMES AFTER PCB EXPOSURE HAVE BEEN REPORTED, FEW MECHANISTIC STUDIES HAVE ADDRESSED THESE DIFFERENCES. WE REPORTED THAT LIVERS FROM HFD-FED MALE MICE WITH MASH AFTER A SINGLE ORAL EXPOSURE TO AN ENVIRONMENTALLY-RELEVANT MIXTURE OF NON-DIOXIN-LIKE PCBS, AROCLOR1260 (AR1260), AND THE DIOXIN-LIKE PCB126 SHOWED INCREASED N(6)-METHYLADENOSINE (M6A), THE MOST COMMON RNA MODIFICATION, THAT REGULATES TRANSCRIPT STABILITY AND ALTERNATIVE SPLICING (AS). WE IDENTIFIED M6A IN APOB (APOLIPOPROTEIN B) AND OTHER MASLD-RELATED TRANSCRIPTS USING M6A MRNA IMMUNOPRECIPITATION (RIP)-SEQUENCING AND CONFIRMED SELECT M6A-DIFFERENTIALLY EXPRESSED GENES USING NANOPORE DIRECT RNA-SEQ. IN AML12 MOUSE HEPATOCYTES. REDUCED APOB PROTEIN IS CRITICAL FOR HEPATIC LIPID ACCUMULATION IN HUMAN MASLD. APOB IS CONSTITUTIVELY TRANSCRIBED, SUGGESTING THAT POST- TRANSCRIPTIONAL REGULATION AND PROTEIN STABILITY DETERMINE APOB LEVELS. THESE DATA SUPPORT OUR OVERARCHING HYPOTHESIS THAT PCB EXPOSURES AND DIET ALTER M6A TO REGULATE LIPID METABOLISM PATHWAYS IN MASLD. WE ADDRESS A CRITICAL KNOWLEDGE GAP IN HOW DIET, ENVIRONMENTAL POLLUTANT EXPOSURES, AND SEX MODIFY THE M6A EPITRANSCRIPTOME TO REGULATE APOLIPOPROTEIN HOMEOSTASIS. WE WILL 1) DETERMINE IF THE ALTERED M6A MARKS IN THE APOB TRANSCRIPT WITH PCB EXPOSURES REGULATE TRANSCRIPT STABILITY AND TRANSLATION. 2) DETERMINE HOW SEX AND DIET IMPACT M6A MARKS IN LIPOPROTEIN TRANSCRIPTS IN A HIGH FAT, HIGH FRUCTOSE DIET (HFHFD) + PCB EXPOSURE MODEL OF MASH. 3) IDENTIFY THE EXTENT OF M6A-INDUCED ALTERNATIVE SPLICING (AS) IN LIVERS IN HFHFD-FED MICE WITH PCB EXPOSURES. THE RESULTING DATA WILL BE THE FIRST TO DIRECTLY EXAMINE HOW MA6-CONTAINING APOB REGULATES PROTEIN ABUNDANCE AFFECTING HEPATIC LIPID PATHOLOGY. DETERMINING THE MECHANISTIC INTERPLAY OF M6A, DIET, AND PCB EXPOSURES IN PROMOTING NAFLD PROGRESSION WILL REVEAL POSSIBLE TARGETS FOR THERAPEUTIC INTERVENTION.

University Of Louisville

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]

Kentucky United States

State-Wide

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