U01AG072572

Alzheimer Variants: Propagation of Shared Functional Changes Across Cellular Networks - Project Abstract

Genetic studies of Alzheimer's disease (AD) and related diseases (ADRD) have identified over 72 loci associated with susceptibility. Although some of the most penetrant variants have been studied independently, the majority of sequence variants and features are unlikely to act in isolation.

In addition, the range of susceptibility loci covers coding, epigenetic, and regulatory regions of the genome, suggesting complex relationships that cannot be captured by large-scale transcriptomic and proteomic profiling alone. With this in mind, we systematically interrogate combinations of variants across validated AD loci in a cell autonomous and non-autonomous manner using a combination of molecular, epigenetic, and functional assays.

This allows us to create a functional network across AD loci and identify nodal points where the effects of individual loci interact to trigger the hallmarks of AD pathology and clinical phenotypes.

As part of this effort, we propose to establish a novel AD locus annotator interface that synthesizes information about AD-associated sequence features from reference databases encompassing existing multi-omic and clinical data, as well as new data sets that capture quantitative proteoform and cellular functional data. These latter two data modalities have been under-characterized in AD research to date but are crucial to identifying cross-loci interactions.

From this synthesized data analysis and portal effort, we then establish a set of gene editing efforts to validate and extend our mechanistic understanding of multi-locus functional networks from these AD-associated sequence features.

Taken together, these analyses and experiments allow us to link the heterogeneity of AD-associated genetic variation and clinical manifestations into a coherent framework that links AD loci with the temporal sequence of events in AD onset and progression.

The Trustees Of Columbia University In The City Of New York

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

Alzheimers Disease Sequencing Project Functional Genomics Consortium (U01 Clinical Trial Not Allowed) (RFA-AG-21-006)

Amendment Since initial award the total obligations have increased 410% from $1,676,096 to $8,542,236.