RF1AG074010

Dissect the Interplay Between Sex and APOE at the Single Cell Level to Uncover Novel Pathways, Targets, and Therapeutics for Alzheimer's Disease - Project Summary

Alzheimer's Disease (AD) is a multifactorial disorder with complex etiologies, and the impact of sex on AD varies over the course of clinical and neuropathological development. Basic and clinical research studies support sex-specific contributions to AD pathogenesis and progression. The apolipoprotein E4 (APOE4) allele has been identified as a primary genetic risk factor. The interplay between sex and APOE4 allele in AD risks, clinical manifestation, pathological processes, as well as treatment responsiveness in various clinical trials have been explored. However, the molecular mechanisms underlying sex dimorphism in AD and how APOE4 stratifies sex divergence in AD remain elusive.

Multi-omics data in tandem with systems biology approaches offer a new avenue to not only dissect sex- and APOE-stratified molecular mechanisms of AD but also develop sex-specific diagnostic and therapeutic interventions for AD. Single-cell transcriptomic datasets as well as cell deconvolution of bulk tissue transcriptomes provide in-depth insights into brain region-specific and cell-type specific impact on sex dimorphism in AD.

In this application, we propose to develop sex- and APOE-specific network models of AD by performing integrative multiscale network analysis of large-scale bulk and single multi-omics data. In particular, we will develop the first cohort of single nucleus multi-omics data in AD (simultaneous RNA-sequencing and ATAC-sequencing of each single cell) that can meaningfully be stratified by sex and APOE genotype. We will also curate existing single nucleus RNA-seq datasets in AD and combine them with our own single-cell multi-omics dataset to identify sex-specific genetic variants and molecular signatures of AD (Aim 1).

We will perform integrative network analysis to investigate the interplay between sex and APOE genotypes in AD at brain-region and single-cell levels and identify, from the network models, sex- and APOE-specific network drivers for AD (Aim 2). We will then identify potential therapeutics of selected key drivers with drug candidate prediction through virtual clinical trials of large electronic medical record (EMR) databases (Aim 3). Finally, we will functionally validate the top predicted sex- and APOE-specific molecular network drivers by genetic manipulations (up- or down-regulation of gene expression), as well as pharmacological perturbation with drug candidates identified from virtual drug screening using relevant human IPSC culture systems and AD mouse models (Aim 4).

The findings from this project will guide the future development of efficacious sex- and APOE-stratified interventions for AD.

Icahn School Of Medicine At Mount Sinai

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

Integrative Research to Understand the Impact of Sex Differences on the Molecular Determinants of AD Risk and Responsiveness to Treatment (R01 Clinical Trial Optional) (RFA-AG-21-029)

Amendment Since initial award the total obligations have decreased from $3,641,905 to $3,618,718.