RF1AG088625

REGULATED CGAS ACTIVATION IN HSV-1-ASSOCIATED NEUROPATHOGENESIS. - TITLE: REGULATED CGAS ACTIVATION IN HSV-1-ASSOCIATED NEUROPATHOGENESIS DEMENTIA IS CHARACTERIZED BY A PROGRESSIVE LOSS IN MEMORY AND COGNITION. ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON DEMENTIA THAT HAS AGING AS THE MOST SIGNIFICANT RISK FACTOR. GENETICS PLAYS A MAJOR ROLE IN AD DEVELOPMENT AND PROGNOSIS, WHICH IS FURTHER INFLUENCED BY ENVIRONMENTAL FACTORS, SUCH AS MICROBIAL INFECTION. HERPES SIMPLEX VIRUSES (HSV) ARE UBIQUITOUS PATHOGENS IN THE HUMAN POPULATION AND REACHES NEARLY 100% IN CITIZENS OF 65 OR OLDER. HSV-1 IS A NEUROTROPIC LARGE DNA VIRUS AND IMPLICATED IN AD DEVELOPMENT, REPRESENTING A MAJOR ENVIRONMENTAL FACTOR FOR AD AND AD-RELATED DEMENTIA. INFLAMMATION IS A COMMON FEATURE OBSERVED IN BRAINS OF BOTH AD MODEL MICE AND HUMAN AD PATIENTS. ONE PATHWAY TRIGGERING INFLAMMATION IN THE BRAIN IS THE CYTOSOLIC DNA-MEDIATED ACTIVATION OF CGAS AND DOWNSTREAM INFLAMMATORY RESPONSE. THOUGH EMERGING STUDIES IMPLICATE CYTOSOLIC DNA AND CGAS IN THE DEVELOPMENT OF AD AND ADRD VIA PROVOKING INFLAMMATION, A NUMBER OF PRESSING QUESTIONS REMAIN UNANSWERED. CENTRAL TO THESE UNANSWERED QUESTIONS IS THE NATURE OF CYTOSOLIC DNA AND THE REGULATION OF DNA-CGAS-MEDIATED INNATE IMMUNE ACTIVATION. THIS PROPOSAL WILL ADDRESS THIS QUESTION WITH A DE NOVO SYNTHESIZED DNA-PROTEIN CROSSLINKER TO PROFILE THE CYTOSOLIC CGAS-BINDING DNA IN HSV-1-INFECTED BRAIN AND PROBE THE DYNAMIC REGULATION OF CGAS ACTIVATION BY A METABOLIC ENZYME. THIS METABOLIC ENZYME PLAYS PIVOTAL ROLES IN REGULATING CGAS ACTIVATION AND DOWNSTREAM INFLAMMATORY RESPONSE. OUR WORK IS EXPECTED TO REVEAL MOLECULAR DETAIL OF CGAS ACTIVATION AND REGULATION BY A METABOLIC ENZYME IN THE NEURODEGENERATION INDUCED BY A UBIQUITOUS HUMAN PATHOGEN.

University Of Southern California

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]

California United States

State-Wide

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