Project Grant R01AG085344

SPATIALLY RESOLVED MULTI-OMICS PROFILING OF HUMAN HIPPOCAMPUS IN AGING AND ALZHEIMER'S DISEASE - PROJECT SUMMARY HUMAN HIPPOCAMPUS IS AMONG THE MOST COMPLEX TISSUE TYPES WITH A WIDE RANGE OF CELLS ORGANIZED IN SPATIALLY PRECISELY DEFINED REGIONS. ALZHEIMER'S DISEASE (AD) IS ONE OF THE DISEASES STRONGLY AFFECTED THE HIPPOCAMPAL REGION, WHICH UNDERLIES THE CORE FEATURE OF THE DISEASE-MEMORY IMPAIRMENT AND REMAINS REFRACTORY TO THERAPY, DUE IN PART TO THE COMPLEXITY OF GENE REGULATORY NETWORK COUPLED WITH CELL-TYPE-SPECIFIC MECHANISMS OF AD PROGRESSION. WHAT TYPES OR SUBTYPES OF CELLS ARE AFFECTED BY THIS PROCESS AND THEIR SPATIAL HETEROGENEITY IN THE TISSUE CONTEXT AS WELL AS HOW THESE CELLS IMPACT THE TISSUE ENVIRONMENTS REMAIN POORLY UNDERSTOOD, WHICH PRECLUDES THE DEVELOPMENT OF STRATEGIES TO TARGET THESE CELLS TO IMPROVE HEALTHSPAN/LIFESPAN OR HARNESSING THESE CELLS TO PROMOTE TISSUE REMODELING AND REPAIR, HIGHLIGHTING A PRESSING NEED FOR TOOLS TO MAP CELLS AND THE SURROUND MICROENVIRONMENTS IN THESE TISSUES AND GENERATE BIOMARKERS TO DEFINE SPATIAL AND PHENOTYPIC HETEROGENEITY IN AD. THIS GRANT AIMS TO (1) DEVELOP A FIRST-OF-ITS-KIND TECHNOLOGY FOR SPATIAL CO-PROFILING OF EPIGENOME, TRANSCRIPTOME, AND A PANEL OF PROTEINS IN THE SAME TISSUE SECTION, AND (2) DEPLOY THE HIGH-RESOLUTION, HIGH-CONTENT AND HIGH-THROUGHPUT SPATIAL MULTI-OMICS TECHNOLOGIES TO CONSTRUCT COMPREHENSIVE MAPS OF CELLULAR STATES AND THE ASSOCIATED ENVIRONMENTS IN HUMAN HIPPOCAMPUS FROM AD PATIENTS AND HEALTH DONORS. THE EXPECTED OUTCOMES AND THE MAJOR CONTRIBUTIONS OF OUR PROJECT INCLUDE: (1) FUNDAMENTAL KNOWLEDGE ON DIVERSE CELL TYPES AND THEIR MOLECULAR BASIS OF SELECTIVE VULNERABILITY (AND CONVERSELY THE RESILIENCE OF OTHER CELL TYPES) IN THE CONTEXT OF TISSUE ORGANIZATION IN THE AD HUMAN HIPPOCAMPUS, ALLOWING US TO DEVELOP A HIGH-SPATIAL-RESOLUTION CELL CENSUS WHICH WILL IN TURN ALLOW US TO IDENTIFY MOLECULAR SIGNATURE PATTERNS, GENE REGULATORY NETWORKS, AND BIOLOGICAL PROCESSES POTENTIALLY MEDIATING CELL TYPE SPECIFIC DIFFERENCES IN THE AD, AND (2) OFFER THE POSSIBILITY OF TESTING NEW THERAPEUTIC APPROACHES FOR AD THAT ARE NOT TARGETED BY CURRENTLY APPROVED TREATMENTS. THE RESULTING DATA WILL LEAD TO BETTER UNDERSTANDING OF THE RELATIONSHIP BETWEEN TISSUE ORGANIZATION, FUNCTION, AND GENE REGULATORY NETWORKS IN AD.