R01AG069900

Drug Repositioning for Alzheimer's Disease via Genetics, Electronic Health Records, and Human iPSC Models

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia in the United States. Unfortunately, there is no cure for AD. Drug discovery for AD has suffered significant failures, many at late-stage clinical trials, partly due to our poor understanding of AD pathology and the lack of disease-relevant and human-relevant discovery and development models. This calls for team efforts with diverse and complementary expertise to tackle the challenges together, by developing innovative approaches from multiple angles to achieve the goal of identifying AD drugs.

In this application, we propose three complementary specific aims that together aim to identify FDA-approved drugs with repurpose potential for AD, from distinct but complementary angles that act synergistically to boost the likelihood of success.

AD is a highly heritable disease, with an estimated heritability of 70%, highlighting the critical role of genetics in understanding the disease etiology. Recent genetic studies have identified over 30 loci, enabling us to dissect the genetic architecture of AD, including the biological processes and cell types involved in disease etiology. In particular, we aim to dissect the highly polygenic AD etiology into distinct pathophysiological components to guide drug repurposing, which is only feasible in recent years thanks to large-scale GWAS and massive genomics data available publicly (Aim 1).

In parallel, we will mine millions of electronic health records (EHRs) to identify drugs that reduce AD risk and cognitive decline, by developing phenotyping algorithms from EHR for AD-related phenotypes (Aim 2).

In addition, we will develop a high-throughput screening (HTS) gene expression profiling assay and use human induced pluripotent stem cell (iPSC) models to identify candidate compounds, and will further test the efficacy of the candidates in both patient-derived iPSC lines and AD mouse models (Aim 3).

The three aims are complementary and synergistic, in the sense that they independently tackle the same problem from drastically distinct angles, while findings from one can be served as validation for others. Altogether, leveraging distinct and complementary expertise, we expect to yield bona fide repurposable drugs for AD with orthogonal support.

Vanderbilt University

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]

Nashville, Tennessee 37203 United States

Single Zip Code

Translational Bioinformatics Approaches to Advance Drug Repositioning and Combination Therapy Development for Alzheimers Disease (R01) (PAR-17-032)

Amendment Since initial award the total obligations have increased 374% from $838,304 to $3,970,571.