U01AG073323

Alzheimer's Multiome Data Repurposing: Artificial Intelligence, Network Medicine, and Therapeutics Discovery - Project Summary

Predisposition to AD involves a complex, polygenic, and pleiotropic genetic architecture; furthermore, there are no disease modifying treatments that slow the neurodegenerative process for AD. Traditional reductionist paradigms overlook the inherent complexity of AD and have often led to treatments that lack clinical benefits or are fraught with adverse effects.

Existing multi-omics data resources, including genetics, genomics, transcriptomics, interactomics (protein-protein interactions and chromatin interactions), have not yet been fully utilized and integrated to explore the pathobiology and drug discovery for AD. Understanding AD genetics and genomics from the point-of-view of how cellular systems and molecular interactome perturbations underlie the disease (termed disease module) is the essence of network medicine. Systematic identification and characterization of novel underlying pathogenesis and disease module will serve as a foundation for identifying and validating novel risk genes and drug targets in AD.

Given our preliminary results, we posit that a genome-wide, multimodal artificial intelligence (AI) framework to identify new risk genes and networks from human genome/exome sequencing and multi-omics findings enable a more complete mechanistic understanding of AD pathogenesis and the rapid development of targeted therapeutic intervention for AD with great success.

Aim 1 will determine whether rare coding and non-coding variants by whole-genome/exome sequencing (WGS/WES) are enriched in protein-functional and gene-regulatory regions using sequence and structure-based deep learning models. These analyses will assemble WGS/WES and clinical data from Alzheimer's Disease Sequencing Project (ADSP), publicly available protein structure (i.e., protein-protein interfaces, protein-ligand binding sites, post-translational modifications) and sequence (expression quantitative trait locus [eQTLs], histone-QTLs, and transcription factor binding-QTLs) information from the PDB database, GTEx, NIH Roadmap, FANTOM5, PsychENCODE, and NIH 4D Nucleome.

Aim 2 will determine whether GWAS common variants linked to AD pathobiology and endophenotypes are enriched in gene regulatory networks in a cell-type specific manner using a Bayesian framework. We will validate risk gene and network findings using WGS/WES and protein panel expression data from our existing cohorts: the Cleveland Clinic Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease Biobank (CBH-BIOBANK) and the Cleveland Alzheimer's Disease Research Center (CADRC).

Aim 3 will test the hypothesis that risk genes and networks can be modulated via in silico drug repurposing, population-based validation, and functional test, to identify candidate agents and drug combinations that will modify AD.

The successful completion of this project will offer capable and intelligent computer-based toolboxes that enable searching, sharing, visualizing, querying, and analyzing genetics, genomics, and multi-omics profiling data for genome-informed therapeutic discoveries for AD and other neurodegenerative diseases if broadly applied.

Cleveland Clinic Lerner College Of Medicine Of Case Western Reserve University

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]

Cleveland, Ohio 44195 United States

Single Zip Code

Cognitive Systems Analysis of Alzheimer's Disease Genetic and Phenotypic Data (U01 Clinical Trial Not Allowed) (PAR-19-269)

Amendment Since initial award the total obligations have increased 300% from $796,538 to $3,186,152.