R01AG074003

Single-Cell Epigenomic and Transcriptional Dissection of Sex-Specific Differences in Alzheimer's Disease - Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that leads to dramatic effects on the affected individuals and their families. While the characterization of the genetic contribution to AD and underlying molecular mechanisms have advanced the understanding of the disease in recent years, studies show that sex differences account for much of the observed differences in risk, progression, and severity across individuals.

Here, we directly dissect the contribution of sex-specific variation down to the region-specific and cell-type-specific molecular basis by systematic profiling, computational integration, and experimental validation of the transcriptional, epigenomic, and genetic signatures across individuals, brain regions, and cell types.

In Aim 1, we use genetic, epigenomic, and transcriptional profiles, generating millions of single-cell (SC) level maps using scRNA-seq and scATAC-seq across human and mouse samples of varying ages and genetic risk status.

In Aim 2, we analyze the resulting datasets in the context of known AD genetic risk variation and underlying molecular mechanisms, enabling us to discover and converge variants, regulatory regions, genes, pathways, cell types, and brain regions to functional, causal mechanisms that drive sex-related differences.

In Aim 3, we use our well-established mouse and iPSC models to test our predicted mechanisms with both high-throughput and cell-type specific assays.

The resulting datasets, computational predictions, and experimentally-supported mechanisms will shed light on the sex-related differences of AD and will help deepen our understanding of the disease in general as we develop more personalized therapeutic approaches in treating AD.

Massachusetts Institute Of Technology

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]

Cambridge, Massachusetts 021394309 United States

Single Zip Code

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 increased 406% from $1,076,916 to $5,445,522.