R01AG070830

Contributions of Astrocyte RELA Signaling in Aging-Related Neurodegenerative Sequelae Following TBI - Abstract

Traumatic brain injury (TBI) is significantly correlated with increased risk for developing several neurodegenerative disorders, including Alzheimer's disease (AD) and AD-related dementia (ADRD), representing one of the most powerful environmental risk factors for AD/ADRD. Compounding these correlates is that aging is a substantial factor in the incidence and vulnerability to TBI.

Owing to the complexities surrounding TBI as a progressive neurodegenerative disorder leading to AD/ADRD, the cellular mechanisms potentially underlying the aging brain's susceptibility to acquire degenerative responses remains elusive. To date, the bulk of published findings related to TBI-related Alzheimer's-like impairments have been examined using young adult and predominantly male rodents, which does not accurately model the greatest at-risk population in humans.

However, our aging TBI model recapitulates several correlates of Alzheimer's-like impairments including chronic memory impairment, exacerbated neuroinflammation, gliosis, phosphorylated tau, as well as microglial phenotypes previously documented in both humans and mouse models of Alzheimer's disease.

Guided by preliminary findings, our overarching hypothesis is that in the aging brain following TBI, RELA drives exacerbated astrocyte responses, underlying the aging brain's susceptibility for persistent decremental outcomes related to homeostatic astrocyte susceptibility, neuroinflammation, and neural network dysfunction. We believe these altered responses, initiated by TBI in the aging brain, ultimately manifest in correlates characteristic of progressive neurodegeneration associated with AD/ADRD.

We will pursue three aims to test this hypothesis using novel genetic models for targeting astrocytes in young and aged mice to determine:

1. The susceptibility of aged astrocytes to lose critical homeostatic features following TBI.
2. The ability of astrocytes to regulate the conversion of microglia towards decremental AD-associated inflammatory phenotypes following TBI.
3. The role of astrocytes in the vulnerability of synaptic circuitry and impaired memory, a critical hallmark associated with TBI/ADRD.

Cumulatively, these studies will help to elucidate both the cellular and molecular substrates through which the aging brain's response to TBI facilitates progressive neurodegenerative sequelae that can eventually lead to AD/ADRD. Our salient findings will ultimately determine the extent to which RELA is a critical mediator in these AD-associated sequelae with the potential to elucidate new therapeutic targets toward their prevention.

University Of Kentucky Research Foundation

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]

Kentucky United States

State-Wide

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 398% from $665,337 to $3,313,377.