Graduation Year

2022

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biomedical Engineering

Major Professor

Robert Frisina, Ph.D.

Committee Member

Bo Ding, M.D.

Committee Member

Victoria Sanchez, Ph.D.

Committee Member

Mark Jaroszeski, Ph.D.

Committee Member

Nathan Gallant, Ph.D.

Keywords

Aging, Connexins, Presbycusis, Kir4.1, Drug Development

Abstract

Age-related hearing loss (ARHL), also known as presbycusis, is the number one communication disorder affecting our aged population. Connexin proteins are essential for intercellular communication throughout the human body. Mutations in connexin genes have been linked to human syndromic and nonsyndromic deafness; thus, we hypothesize changes in connexin gene and protein expression with age may be involved in the development of ARHL. In our current study, connexin mRNA gene expression for CBA/CaJ mice at different age points were examined and correlations were analyzed between the changes in gene expression and functional hearing measures, such as ABRs and DPOAEs. Moreover, we investigated potential treatment options for ARHL. Results showed significant downregulation of Cx30 and Cx43 gene expression in the stria vascularis (SV), and meaningful correlations between the degree of hearing loss and the changes in gene expression for both genes. Moreover, dose-dependent treatments utilizing cochlear cell lines showed that H2O2 oxidative stress significantly decreased gene and protein expression for Cx30 and Cx43, while aldosterone hormone therapy significantly increased Cx expression. In vivo treatment of aging mice with aldosterone also revealed protective effects on connexin expression and ARHL. These findings support further quantitative analyses for measuring the exact effects of each treatment. Based on these functionally relevant findings, our goal is to determine more about the mechanisms related to connexin family gap junction protein expression changes during ARHL, and expand our knowledge of potential, innovative treatment options.

Download

Share

COinS