R01AG086467

FUNGEN-XQTL: UNRAVELING THE GENETIC BASIS OF MOLECULAR FUNCTIONS IN ALZHEIMER'S DISEASE - PROJECT SUMMARY IN THIS PROJECT, WE PROPOSE TO IDENTIFY CAUSAL GENES, CELL TYPES, AND MOLECULAR MECHANISMS IN ALZHEIMER’S DISEASE (AD) BY LEVERAGING GENETICS AS NATURAL PERTURBATION EXPERIMENTS ACROSS MULTI-OMICS DATA — A UNIQUE APPROACH TO ESTABLISH CAUSALITY IN HUMAN BRAIN SAMPLES WHERE EXPERIMENTAL MANIPULATION IS NOT POSSIBLE. BUILDING UPON THE SUCCESSFUL PILOT PHASE OF THE ADSP FUNCTIONAL GENOMICS CONSORTIUM XQTL PROJECT (FUNGEN-XQTL), WE INTEGRATE MULTI-ANCESTRY MOLECULAR QUANTITATIVE TRAIT LOCI (XQTL) ACROSS BRAIN CELLS, CEREBROSPINAL FLUID (CSF), AND BLOOD TO ADDRESS KEY CHALLENGES IN AD GENETICS: DETERMINING CAUSAL RELATIONSHIPS BETWEEN BRAIN AND BLOOD REGULATION, IDENTIFYING DISEASE-RELEVANT CELL CONTEXTS, AND BRIDGING THE GAP BETWEEN GWAS FINDINGS AND MOLECULAR MECHANISMS. OUR APPROACH COMBINES DEEP MOLECULAR PROFILING OF UNDERSTUDIED BRAIN CELL POPULATIONS WITH ADVANCED COMPUTATIONAL METHODS ACROSS FOUR SPECIFIC AIMS: (1) GENERATING AND FINE-MAPPING MOLECULAR QTL IN RARE BRAIN CELL TYPES ACROSS ANCESTRIES, WITH UNPRECEDENTED PROFILING OF 450 AFRICAN AMERICANS AND 350 HISPANIC INDIVIDUALS; (2) INTEGRATING XQTL DATA FROM BRAIN, CSF, AND BLOOD TO UNCOVER COORDINATED NEUROVASCULAR REGULATION AND CAUSAL RELATIONSHIPS BETWEEN TISSUES IN AD; (3) DEVELOPING ADVANCED COMPUTATIONAL METHODS INCLUDING AI-POWERED PREDICTION AND CAUSAL MULTI-CONTEXT ANALYSIS TO IDENTIFY DISEASE-CAUSING GENES AND THEIR RELEVANT CELLULAR CONTEXTS; AND (4) INVESTIGATING MOLECULAR MECHANISMS OF PRIORITIZED TARGETS THROUGH SYSTEMATIC FUNCTIONAL STUDIES USING HUMAN IPSCS. THE IMPACT EXTENDS BEYOND CREATING A COMPREHENSIVE MULTI-ANCESTRY XQTL RESOURCE – OUR SYSTEMATIC APPROACH TO DISENTANGLE COMPLEX REGULATORY MECHANISMS WILL ESTABLISH PRECISE CELLULAR AND MOLECULAR TARGETS FOR THERAPEUTIC DEVELOPMENT IN AD AND RELATED DEMENTIAS.

The Trustees Of Columbia University In The City Of New York

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]

New York United States

State-Wide

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