R01ES037968

INTEGRATING THE EXPOSOME AND EPIGENOME IDENTIFIES DETERMINANTS OF ALS RISK, SURVIVAL, AND PATHOGENESIS - ABSTRACT AMYOTROPHIC LATERAL SCLEROSIS (ALS) IS A FATAL NEURODEGENERATIVE DISEASE WITH NO CURE OR MEANINGFUL TREAT- MENTS. ALS IS MOSTLY SPORADIC, AND FOR MOST, EVIDENCE SUPPORTS A GENE-TIME-ENVIRONMENT HYPOTHESIS OF ALS TRIGGERED BY A CONFLUENCE OF NONMODIFIABLE RISK FACTORS (AGE, SEX, AND GENETICS) AND MODIFIABLE RISK FACTORS FROM THE EXPOSOME (A PERSON’S CUMULATIVE LIFETIME EXPOSURES). EXPOSURES IMPRINT ON THE EPIGENOME VIA DNA METH- YLATION (DNAM) MARKS, WHICH CHANGE WITH AGE, MODIFYING CELLULAR RESPONSE TO ENVIRONMENTAL INSULTS. COMPRE- HENSIVE KNOWLEDGE OF ALL THESE FACTORS IS NEEDED TO DEVELOP PERSONALIZED PREVENTION STRATEGIES FOR THOSE AT HIGHEST RISK AND PERSONALIZED THERAPEUTICS FOR THOSE ALREADY LIVING WITH ALS. WE REPORTED THAT BIOFLUID- AND SUR- VEY-BASED EXPOSURE MEASURES, SUMMARIZED BY ENVIRONMENTAL RISK SCORES (ERS), STRONGLY IMPACT ALS RISK AND PROGRESSION, ADJUSTED FOR GENETIC BACKGROUND. WE ALSO RECENTLY DISCOVERED THAT EPIGENETIC AGE ACCELERATION, CALCULATED FROM DNAM, IS ASSOCIATED WITH ALS RISK AND EXPOSURES. HOWEVER, THE FULL SPECTRUM OF NONMODIFIA- BLE AND MODIFIABLE RISK FACTORS RESULTING CHANGES IN THE EPIGENOME ARE INCOMPLETELY CHARACTERIZED. THERE IS A CRITICAL NEED TO FILL THIS GAP AND DETERMINE HOW THESE FACTORS IMPACT ALS RISK AND THE EPIGENOME, LEADING TO A BETTER UNDERSTANDING OF DISEASE ETIOLOGY, WHICH CAN INFORM FUTURE PRECISION STRATEGIES TO PREVENT ALS. OUR LONG-TERM GOAL IS TO LEVERAGE KNOWLEDGE OF THE ALS EXPOSOME TO INFORM PERSONALIZED ALS PREVENTION AND THERAPEUTIC STRATEGIES. OUR CURRENT OBJECTIVES ARE TO (I) COMPREHENSIVELY ASSESS THE EXPOSOME IN OUR MICHIGAN COHORT AND DETERMINE HOW IT ASSOCIATES WITH ALS RISK AND SURVIVAL; AND (II) GAIN INSIGHT INTO DISEASE ETIOLOGY BY EXAMINING THE INTERSECTION OF THE EXPOSOME WITH THE ALS EPIGENOME AND TRANSCRIPTOME. OUR CENTRAL HYPOTHE- SIS IS THAT ALS CASES WILL HAVE HIGHER ERS SCORES, WHICH CORRELATE WITH EPIGENETIC AND TRANSCRIPTOMIC CHANGES AND ALS RISK AND SURVIVAL. IN AIM 1, WE WILL LEVERAGE TARGETED AND UNTARGETED EXPOSOMICS IN BIOFLUIDS TO IDENTI- FY TOXICANT EXPOSURES THAT ASSOCIATE WITH ALS RISK AND SURVIVAL AND DETERMINE THE EFFECTS OF AGE, SEX, AND POL- YGENIC RISK ON THESE OUTCOMES. IN AIM 2, WE WILL IDENTIFY GEOSPATIAL- AND SURVEY-BASED EXPOSOMIC MEASURES LINKED TO ALS RISK AND SURVIVAL, AND EVALUATE HOW THEY ASSOCIATE AGE, SEX, POLYGENIC RISK, AND BIOFLUID TOXICANT MEASURES. FINALLY, IN AIM 3, WE WILL CHARACTERIZE EXPOSOME-RELATED DNAM AND TRANSCRIPTOMIC SIGNATURES AND THEIR ASSOCIATION TO ALS RISK AND SURVIVAL. COMPLETION OF THESE STUDIES WILL IDENTIFY ALS-RELEVANT EXPOSOME FAC- TORS THAT ASSOCIATE WITH TO DISEASE RISK AND SURVIVAL VIA DNAM AND CONSEQUENT TRANSCRIPTOMIC CHANGES. THESE RESULTS WILL HAVE IMPORTANT TRANSLATIONAL IMPACT BY LENDING INSIGHT INTO ALS ETIOLOGY AND IDENTIFYING EXPOSOMIC FACTORS THAT MOST IMPACT ALS RISK AND SURVIVAL, THEREBY MAKING THE FIRST CRITICAL STEPS TOWARDS PERSONALIZED RISK PREDICTION AND PREVENTION STRATEGIES IN ALS BY EXPOSURE MITIGATION.

Regents Of The University Of Michigan

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]

Ann Arbor, Michigan 481091276 United States

Single Zip Code

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