R01AG073151

The Role of POU4F3 in Age-Related Vestibular Dysfunction - Project Summary:

It has been estimated that more than 40% of older adults suffer vestibular (i.e. balance) deficits. These losses cause numerous other problems associated with aging, including cognitive decline and injurious or fatal falls. There is also a strong link between age-related vestibular dysfunction (ARVD) and Alzheimer's disease and related dementias. Despite the prevalence of these issues and the massive toll they exert on public health and associated financial costs, the underlying causes for ARVD are poorly understood. As a result, there are currently no FDA approved therapies for ARVD.

While a deep understanding of mechanistic causes is lacking, it has been known for some time that a very common pathology that causes age-related inner ear dysfunction is the death of sensory cells called hair cells. Exactly why these cells die with age remains a mystery. Here, we have identified a previously uncharacterized pattern in the expression of the pro-survival gene, POU4F3, where it is normally highly expressed in inner ear hair cells, but is downregulated with age in a fashion that is correlated with hair cell death in the balance organs of the inner ear. Furthermore, preliminary data suggest that deleting POU4F3 causes detrimental phenotypes in vestibular hair cells, exacerbates hair cell death, and leads to significant declines in vestibular function.

We propose to build on these preliminary data by further examining POU4F3 changes in expression in vestibular organs with age and in models of Alzheimer's disease. We will also more thoroughly characterize the effects of POU4F3 deletion to better understand the effects that deletion or hypomorphism have on balance and neurological functions. We also propose to examine genomic regulatory elements in inner ear tissues from young and aged mice to identify causal mechanisms for POU4F3 downregulation with age, as well as possibly discover other key genes involved in aging processes in the inner ear.

Finally, we will test whether overexpression of POU4F3 can prevent sensory cell death and age-related vestibular declines. Our preliminary data suggest that POU4F3 is a promising therapeutic target for preserving balance function in the aging human population. The experiments proposed will determine the validity of that overarching hypothesis and will provide a foundation from which to launch several new investigations into POU4F3-targeted pharmacological and gene therapy approaches for the prevention of age-related vestibular decline.

University Of Mississippi Medical 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]

Jackson, Mississippi 392164500 United States

Single Zip Code

Central and Peripheral Control of Balance in Older Adults (R01 Clinical Trial Optional) (RFA-AG-21-011)

Amendment Since initial award the total obligations have increased 379% from $666,569 to $3,193,066.