R01AG073826

The hippocampal dentate gyrus (DG), critically involved in learning and memory, is a vulnerable region in both age-related cognitive impairment (ARCD) and Alzheimer's disease (AD). Causal upstream signaling mechanisms that lead to AD remain poorly understood.

Across the lifespan, excess reactive oxygen species (ROS) accumulate, causing oxidative damage to proteins, lipids, and DNA. This process is termed oxidative stress (OS). Dietary antioxidants (AOs) normally scavenge excess ROS, preventing OS. Moreover, OS triggers AO defenses, which ultimately yield to AD progression. Yet, to date, clinical trials involving AO supplementation have paradoxically failed, exposing large knowledge gaps in understanding which AO species are depleted, the time course of AO depletion, and the underlying mechanisms.

The AO all-trans retinoic acid (ATRA), a bioactive form of vitamin A (VA), serves a dual role as a ROS scavenger and hormone-like ligand for the retinoic acid receptor (RAR). Ligand binding to RARs is critical for transcriptional regulation of genes containing retinoic acid response elements (RAREs). Recent evidence from rodents has demonstrated an age-dependent homeostatic collapse in hippocampal ATRA levels. Moreover, there is increasing evidence that transcriptional silencing occurs in AD.

To investigate ATRA depletion, we performed a secondary analysis of hippocampal transcriptomic data from post-mortem AD brains. ATRA-sensitive genes were downregulated, accompanied by upregulation of RAR repressors. Moreover, several histone deacetylases (HDACs) were upregulated, providing evidence for epigenetic changes.

Given this strong scientific premise, we hypothesize that both ATRA bioavailability and HDAC inhibition are required to restore ATRA-mediated gene transcription and hippocampal-dependent learning. Therefore, our central hypothesis is that combining vitamin A supplementation and HDAC inhibition (HDACI) maintains hippocampal-dependent learning and RAR-sensitive gene transcription in DG more effectively than HDACI alone.

Using an innovative multidisciplinary approach, we will determine effects of combining VA supplementation with HDAC inhibition on learning and transcription of RAR-sensitive genes in DG cell types. SA1 tests the hypothesis that VA supplementation alleviates AD-related learning deficits and multi-omic signatures in the DG. SA2 tests the hypothesis that HDAC inhibition alleviates AD-related learning deficits and multi-omic signatures in the DG. SA3 tests the hypothesis that combining VA supplementation and HDAC inhibition (VA+HDACI) synergistically alleviates AD-related learning deficits and multi-omic signatures in the DG beyond VA and HDACI alone.

Successful completion of this project will increase knowledge of aberrant transcriptional mechanisms occurring in the DG during AD. Integrating behavioral and multi-omic data, the project will elucidate multi-omic signatures in DG that protect against AD, enable the discovery of new genes necessary for DG function, and determine the value of drug repurposing for an FDA-approved HDAC inhibitor.

Texas Tech University Health Sciences Center

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]

Lubbock, Texas 794306592 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 391% from $636,809 to $3,127,581.