RF1AG091181

MAPPING GENETIC VULNERABILITY TO OXIDATIVE STRESS IN DEVELOPMENT AND ITS CONSEQUENCES IN AGE-ASSOCIATED COGNITIVE DECLINE USING A NOVEL REDUCED COMPLEXITY RAT MODEL - ABSTRACT IN THIS PROPOSAL WE TEST THE NOVEL HYPOTHESIS THAT INTRINSIC CELLULAR VULNERABILITY TO OXIDATIVE STRESS (OS) CONTRIBUTES TO PREMATURE COGNITIVE DECLINE AND IS AN IMPORTANT DETERMINANT OF COGNITIVE HEALTH OVER THE LIFESPAN. OS IS KNOWN TO INCREASE WITH AGE AND IS ALSO ASSOCIATED WITH ALZHEIMER’S DISEASE (AD) AND DEMENTIA. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING THESE ASSOCIATIONS ARE NOT WELL UNDERSTOOD. MOREOVER, WE KNOW LITTLE ABOUT WHICH CELL TYPES, MOLECULAR PROCESSES, AND GENOTYPES ARE THE MOST VULNERABLE TO THE DETRIMENTAL EFFECTS OF OS ON COGNITIVE FUNCTION ACROSS THE LIFESPAN. THIS LACK OF KNOWLEDGE MAY BE ONE REASON WHY CURRENT TREATMENTS FOR AD-RELATED DEMENTIA AND AGE-ASSOCIATED COGNITIVE DECLINE (E.G., ACETYLCHOLINESTERASE INHIBITORS AND NMDA RECEPTOR ANTAGONISTS) HAVE DISAPPOINTING EFFICACY AND ARE UNSUITABLE FOR EARLY INTERVENTION. TO OVERCOME THESE BARRIERS, WE LEVERAGE A NOVEL GENETIC RAT MODEL DEVELOPED BY OUR GROUP, THE WISTAR KYOTO MORE IMMOBILE (WMI) INBRED RAT STRAIN AND ITS NEARLY ISOGENIC CONTROL, THE WISTAR KYOTO LESS IMMOBILE STRAIN (WLI). THE WMI STRAIN DEMONSTRATES INCREASED STRESS REACTIVITY AND ENHANCED DEPRESSION-LIKE BEHAVIOR COMPARED TO THE WLI STRAIN. ONLY ~4,300 SEQUENCE VARIANTS DISTINGUISH BOTH GENOMES CREATING AN IDEAL GENETIC MODEL SYSTEM TO IDENTIFY THE CONTRIBUTION OF NATURALLY OCCURRING GENETIC VARIATION TO PHENOTYPIC DIFFERENCES BETWEEN STRAINS WHILE STILL MODELING SOME OF THE GENETIC DIVERSITY FOUND IN HUMAN POPULATIONS. WE HAVE RECENTLY DEMONSTRATED THAT THE WMI STRAIN EXHIBITS HIGHER INTRINSIC VULNERABILITY TO OS RELATIVE TO THE WLI STRAIN. THIS VULNERABILITY CAN BE DETECTED EARLY IN DEVELOPMENT AT EMBRYONIC DAY 18 (E18) IN HIPPOCAMPUS-DERIVED ASTROCYTES AND NEURONS. WE ALSO SHOWED THAT, RELATIVE TO THE LESS VULNERABLE WLI STRAIN, THE WMI STRAIN EXHIBITS PREMATURE COGNITIVE DECLINE AT MIDLIFE THAT CAN BE REVERSED BY EXPOSURE TO AN ENRICHED ENVIRONMENT (EE) AND EXACERBATED EARLY IN LIFE BY REPEATED STRESS (RS) EXPOSURE. WE HYPOTHESIZE THAT INTRINSIC GENETIC VULNERABILITY TO OS IN WMI, WHICH CAN BE DETECTED EARLY IN LIFE AT E18, CONTRIBUTES TO COGNITIVE FUNCTION DURING AGING AND ACROSS DIFFERENT ENVIRONMENTAL EXPOSURES. WE TEST OUR HYPOTHESIS IN TWO AIMS. IN AIM 1 WE LEVERAGE OUR EFFICIENT REDUCED COMPLEXITY MODEL TO IDENTIFY CELL POPULATIONS AND MOLECULAR PATHWAYS MOST VULNERABLE TO OS AND IDENTIFY THE CAUSAL GENE VARIANT MEDITATING INTRINSIC VULNERABILITY TO OS EARLY IN LIFE AND COGNITIVE DECLINE LATER IN LIFE. IN AIM 2 WE QUANTIFY GENE X ENVIRONMENT (GXE) INTERACTIONS IN OUR MODEL TO DEFINE A SET OF CELLULAR, EPIGENETIC, AND MOLECULAR FEATURES IMPORTANT FOR COGNITIVE FUNCTION AS WELL AS A DETAILED MAP OF HOW THESE FEATURES CONTRIBUTE TO MEMORY PERFORMANCE AS A FUNCTION OF AGE, ENVIRONMENTAL EXPOSURE, SEX, AND GENOTYPE.

University Of Tennessee

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE 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. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH 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.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Tennessee United States

State-Wide

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