RF1AG093965

OLFACTORY DYSFUNCTION AS PREDICTOR OF PM2.5 EXPOSURE PROGRESSION TO DEMENTIA - AMBIENT FINE PARTICULATE MATTER (PM2.5) POLLUTION NOT JUST CORRELATES WITH ALZHEIMER’S DISEASE (AD) AND/OR AD-RELATED DEMENTIA (ADRD) BUT IS ALSO ESTIMATED TO ACCOUNT FOR THE HIGHEST BURDEN OF DEMENTIAS IN HIGH- INCOME COUNTRIES. PM2.5 EXPOSURE IS ALSO ASSOCIATED WITH OLFACTORY IMPAIRMENT (OI), AND THE LATTER IS BELIEVED TO PLAY A ROLE IN THE DEVELOPMENT OF AD/ADRD, ALBEIT A CAUSAL ROLE OF OI IN THE DEVELOPMENT OF AD/ADRD REMAINS TO BE DETERMINED AND NO PUBLICATION HAS INVESTIGATED THE ROLE OF OI IN PM2.5 EXPOSURE-RELATED AD/ADRD YET. THEREFORE, TO ASCERTAIN THE CAUSALITY BETWEEN OI AND AD/ADRD IN OUR STATE-OF-THE-ART MODELING OF PM2.5 POLLUTION WILL OBVIOUSLY ADVANCE OUR UNDERSTANDING OF THE PATHOGENESIS OF BOTH PM2.5 EXPOSURE-RELATED AND - UNRELATED AD/ADRD AND SHED LIGHT ON DEVELOPING INTERVENTION APPROACHES INCLUDING EARLY AND ACCURATE DIAGNOSIS FOR AD/ADRD. OUR PRELIMINARY STUDIES IN MOUSE MODELS RECAPITULATED THE SIGNIFICANT COGNITIVE DECLINE DUE TO CHRONIC PM2.5 EXPOSURE, WHICH WAS CLEARLY PRECEDED BY OI AND PATHOLOGIES OF THE OLFACTORY EPITHELIUM (OE) AND OLFACTORY BULB (OB), NOT JUST SUPPORTING THE CAUSALITY BETWEEN OI AND AD/ADRD BUT ALSO MAKING US TECHNICALLY READY TO DETERMINE THIS CAUSALITY. THROUGH A SYNTHESIS OF RELEVANT PUBLICATIONS AND SEVERAL CRITICAL PRELIMINARY STUDIES, WE HYPOTHESIZE THAT EARLY AFTER PM2.5 EXPOSURE, THE CYCLIC GMP-AMP SYNTHASE (CGAS)/STIMULATOR OF INTERFERON GENES (STING) /INHIBITOR B KINASE 2 (IKK2)/NUCLEAR FACTOR-B (NF- ΚB)-MEDIATED INFLAMMATORY ACTIVATION OF THE OE AFFECTS OLFACTION, HERALDING PROGRESSION TO LATE-ONSET NEURODEGENERATION AND DEMENTIA, AND PROPOSE TO THOROUGHLY TEST THIS HYPOTHESIS THROUGH PURSUING THE FOLLOWING 3 RELEVANT BUT RELATIVELY INDEPENDENT AIMS: AIM 1: DETERMINE WHETHER PM2.5 EXPOSURE-INDUCED OI IS CAUSAL FOR THE LATE-ONSET DEMENTIA; AIM 2: DETERMINE WHETHER PM2.5 EXPOSURE IMPAIRS OLFACTION AND COGNITION VIA THE CGAS/STING/IKK2/NF-B AXIS-DEPENDENT INFLAMMATION AND SUBSEQUENT DEFAULT NEUROGENESIS IN THE OE; AIM 3: DETERMINE WHETHER PM2.5 EXPOSURE ALTERS ODORANT SIGNAL PROCESSING OF THE OB AND WHETHER OLFACTORY TRAINING PROMOTES OB NEUROGENESIS AND AMELIORATES OLFACTORY AND COGNITIVE IMPAIRMENTS INDUCED BY PM2.5 EXPOSURE. THE OVERALL OBJECTIVE OF THIS PROPOSAL IS TO INVESTIGATE THE MECHANISMS UNDERLYING PM2.5 EXPOSURE-INDUCED OI IN A STATE-OF-THE-ART PM2.5 EXPOSURE MODEL AND ITS CORRELATION WITH LATE-ONSET DEMENTIA, AND OUR FINDINGS ARE EXPECTED TO SHED LIGHT ON DEVELOPING NOVEL APPROACHES FOR EARLY AND ACCURATE DIAGNOSIS OF PM2.5 POLLUTION-RELATED OI AS WELL AS NEURODEGENERATION AND LATE-ONSET DEMENTIA.

University Of Maryland, Baltimore

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]

Baltimore, Maryland 21201 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)