R01AG071496

Systematic Modeling and Prediction of Cell-Type-Specific and Spatiotemporal Crosstalk Pathways in Alzheimer's Disease - Abstract

Alzheimer’s disease (AD) affects more than 50 million people worldwide but there is no clear therapeutic option for the patients. For the last two decades, AD research has been focusing on a neuron-centric biochemical process that leads to synaptic deficits and neuronal degeneration. However, recent failures in clinical trials clearly demonstrate a gap in knowledge in our current understanding of AD pathogenesis and call for studies that lead to unbiased and holistic understanding of disease pathways in different types of brain cells.

This project aims to tackle this important and urgent issue by combining a computational systems biology platform, Single-Cell Resolution Brain Interactome (SCRBI) Explorer, 3D human Alzheimer's-in-a-dish models, and the publicly available multiple-omics AD databases through NIH-funded AMP-AD portal. We will expand the knowledge base of SCRBI Explorer to handle single-cell transcriptomic and multiple omics profiles from 3D cell models and human brain tissues, which can detect on multiple layers of neuron-glia and glia-glia crosstalk pathways via ligand-receptor interactions, cytokine/chemokine signaling, intracellular signaling activities, and transcriptional activation.

The central hypothesis is that the combined use of multi-cellular systems biology modeling and 3D human AD cellular models will identify AD-specific neuron-glia and glia-glia crosstalk pathways, which would provide novel therapeutic targets for drug repositioning. We will test this hypothesis by pursuing three specific aims:

1) Develop a multi-cellular crosstalk model to uncover altered neuron-glia and glia-glia crosstalk pathways in AD.
2) Identify and validate AD-specific neuron-glia and glia-glia crosstalk pathways that are enriched in 3D human AD cellular models and human AD brain cells.
3) Evaluate the therapeutic potential of neuron-glia and glia-glia crosstalk using 3D human neural cell culture models of AD.

The potential impact of this proposal is high because the proposed study, if successful, will provide a unique integrated bioinformatics tool to unbiasedly identify neuron-glia and glia-glia crosstalk pathways in AD and even other neurodegenerative diseases. More importantly, it will provide novel therapeutic targets based on altered neuron-glia interaction pathways in AD and open up a new vista for drug repositioning targeting cell-cell interactions in the brain of AD patients.

Methodist Hospital

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]

Houston, Texas 77030 United States

Single Zip Code

Translational Bioinformatics Approaches to Advance Drug Repositioning and Combination Therapy Development for Alzheimers Disease (R01 Clinical Trial Optional) (PAR-20-156)

Amendment Since initial award the total obligations have increased 298% from $790,802 to $3,147,393.