RF1AG090932

ASSESSING THE ROLE OF SEX-SPECIFIC GENETIC DRIVERS OF CEREBROVASCULAR DISEASE IN THE ALZHEIMER'S DISEASE BRAIN - ABSTRACT ALZHEIMER'S DISEASE (AD) DISPROPORTIONATELY AFFECTS WOMEN, YET THE UNDERLYING BIOLOGICAL AND GENETIC FACTORS CONTRIBUTING TO THIS SEX DISPARITY REMAIN POORLY UNDERSTOOD. THIS PROPOSAL ADDRESSES THIS CRITICAL GAP BY FOCUSING ON THE INTRICATE INTERPLAY BETWEEN SEX-SPECIFIC GENETIC FACTORS, CEREBROVASCULAR DISEASE (CVD), AND AD PATHOGENESIS. BUILDING ON OUR GROUNDBREAKING RESEARCH REVEALING SEX-SPECIFIC GENETIC ASSOCIATIONS IN AD- RELATED ENDOPHENOTYPES, WE AIM TO EXTEND THIS PARADIGM TO EXPLORE THE ROLE OF GENETICS IN THE DEVELOPMENT AND PROGRESSION OF CVD WITHIN THE AD-AFFECTED BRAIN AND TO INVESTIGATE WHETHER OR NOT THESE RELATIONSHIPS PRESENT IN A SEX-SPECIFIC MANNER. OUR RESEARCH TEAM, WITH EXPERTISE SPANNING STATISTICAL GENETICS, SEX DIFFERENCES IN ALZHEIMER'S AND RELATED DEMENTIAS, NEUROPATHOLOGY, AND NEUROPSYCHIATRY, WILL HARNESS THE VAST RESOURCES OF THE ALZHEIMER’S DISEASE GENETICS CONSORTIUM AND THE ALZHEIMER’S DISEASE SEQUENCING PROJECT. WITH AUTOPSY DATA FROM OVER 9,600 WELL-CHARACTERIZED PARTICIPANTS, INCLUDING MEASURES OF CVD, AMYLOID AND TAU BURDEN, AND LONGITUDINAL COGNITIVE SCORES, WE ARE UNIQUELY POSITIONED TO CONDUCT THE MOST EXTENSIVE SEX- SPECIFIC GENOME-WIDE ANALYSES OF CVD ENDOPHENOTYPES IN THE CONTEXT OF AD TO DATE. THE SPECIFIC AIMS OF THIS PROPOSAL ARE THREEFOLD: [1] IDENTIFY SEX-SPECIFIC GENETIC MARKERS OF AUTOPSY MEASURES OF BRAIN VESSEL DISEASE (I.E., ATHEROSCLEROSIS AND ARTERIOLOSCLEROSIS), [2] IDENTIFY SEX-SPECIFIC GENETIC MARKERS OF AUTOPSY MEASURES OF VASCULAR BRAIN INJURY (I.E., MACROSCOPIC AND MICROSCOPIC INFARCTION), AND [3] CHARACTERIZE THE DEGREE TO WHICH KNOWN GENETIC DRIVERS OF CVD AFFECT COGNITIVE DECLINE IN A SEX-SPECIFIC MANNER. THE OUTCOME OF THIS PROJECT WILL HIGHLIGHT NEW CANDIDATE PATHWAYS AND BEGIN THE PROCESS OF CHARACTERIZING THE MECHANISMS BY WHICH GENETIC VARIATION AMONG MALES AND FEMALES AFFECTS THE RISK OF CVD AND CLINICAL SYMPTOMS OF AD. IT ALSO HOLDS THE PROMISE OF IDENTIFYING NOVEL THERAPEUTIC TARGETS AND OF MOVING THE FIELD TOWARDS PERSONALIZED INTERVENTIONS THAT CONSIDER AN INDIVIDUAL’S SEX AND NEUROPATHOLOGICAL PRESENTATION.

Vanderbilt University Medical Center

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]

Nashville, Tennessee 37203 United States

Single Zip Code

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