U24AG087563

The BrainCellQTL Consortium: QTL mapping in the human brain at the single cell level - Alzheimer's disease and related dementias (AD/ADRD) progressively impair essential cognitive and mental functions, resulting in significant emotional, physical, and financial burdens.

Genome-wide association studies have identified thousands of loci contributing to the risk of more than a hundred serious mental and neurological disorders (SMND), including AD/ADRD and others such as schizophrenia, Parkinson’s disease and multiple sclerosis.

Integrating risk loci with quantitative trait loci (QTLs) for molecular traits, such as gene expression and epigenome regulation, in human brain tissue, has been widely adopted as an analytical strategy to nominate causal mechanisms for AD/ADRD and SMNDs.

So far, large-scale integrative analyses using this approach have utilized homogenate brain tissue, which is composed of multiple cell types, and therefore cell-type-specific QTLs are not fully captured.

This is an important limitation given that risk variants for AD/ADRD and SMNDs act through cell-type-specific biological mechanisms.

Initial efforts have included cell-type-specific QTL analysis in the human brain by utilizing single-cell data, but the sample size of such studies is hindered by the increased experimental costs.

To overcome these limitations, we propose to establish the Brain Single-Cell XQTL (BrainCellQTL) Consortium that brings together existing resources of more than 10,000 single-cell libraries from more than 3,000 unique brain donors, as well as expertise in single-cell biology, neuroscience, statistical genetics and machine learning, to facilitate the harmonization of brain single-cell data, QTL generation and data sharing with the scientific community.

Activities will be organized around the Synapse Data Platform by Sage Bionetworks, an NIH-designated generalist repository that supports dozens of research consortia, focused on neurodegeneration, neuropsychiatric disease, cancer, rare disease, and other research areas.

The Synapse Data Platform will be utilized to receive data, validate it against metadata and data standards, and harmonize them for downstream analysis.

To increase the reproducibility and transparency of BrainCellQTL Consortium research, we will use Cavatica by Seven Bridges for data processing and analysis.

Cavatica is a secure, scalable, and extendable data commons platform that empowers collaboration and scientific analysis.

Upon successful completion of the proposed research, we expect to construct a cell type-specific QTL atlas for the human brain, which we will use to derive genetically driven gene dysregulation in AD/ADRD and SMNDs, thus, enabling us to: (1) increase our mechanistic understanding of dysfunction in AD/ADRD and SMNDs; (2) better prioritize significant genes and molecular pathways for future mechanistic studies; (3) provide a valuable resource that can be applied in ongoing and future genome-wide association studies; (4) provide preprocessed and harmonized single-nucleus brain omics data that can be utilized by the research community to address other biologically-driven questions; and (5) establish a mechanism for data sharing and harmonization across consortia and projects, which can be utilized in future studies to perform single-cell mega-analyses and meta-analyses.

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, New York 100296504 United States

Single Zip Code

Genomic Community Resources (U24 Clinical Trial Not Allowed) (PAR-23-085)

Amendment Since initial award the total obligations have increased 101% from $2,333,781 to $4,701,117.