Age-related hearing loss (ARHL) or presbycusis is the most prevalent sensory deficit and with the increase in life expectancy, it is predicted to have vast impact in the well-being of our society. Indeed, audition and communication is the essence of our human interactions. The overall framework for this programmatic proposal is that a comprehensive understanding of ARHL is only possible through studies of not only the vulnerable synaptic and neural structures of the inner ear, but also examination of the neural plasticity that occurs in response to changes at the neurites of spiral ganglion neurons. We have brought together expert individuals from genetics to cell biology and physiology (Tempel, Yamoah, Ricci, and Gratton). These investigators have already worked together in a highly synergistic and productive manner. There are three projects (P) served by three Cores (Administrative, Mouse Genetics and Structural Analysis Cores) to test the Central Hypothesis that the aging auditory sensory epithelia undergo structural changes that allow the high K+ endolymph to leak into the perilymph, triggering HC and SGN depolarization, increased intracellular Ca2+ ([Ca2+]i) and subsequent ?silent? synaptic and neuronal degeneration (P2, P3). We predict that structural changes are mediated by weakening tight junctions (TJs) in the aging cochlear sensory epithelium (P1, Core C). Genetic manipulation of Claudin 9 and Occludin, two identified TJ proteins in the sensory epithelium, that show robust reduction in expression levels, will be used as prototypes together with three additional ARHL models to test our hypothesis (P1-3, Cores B-C). We propose that neural and synaptic alterations at the periphery (P2, P3) will mediate cellular changes that confer long-lasting alterations auditory system. The proposed studies will reveal critical neural and synaptic mechanisms of ARHL. New therapeutic targets for the treatment of ARHL will be assessed, tested and proposed, thus, transforming and shifting the prevailing paradigm to mechanistic and translational platforms.

Public Health Relevance

Age-related hearing loss (ARHL) is pervasive and insidious; representing the most common sensory deficit. Indeed, 30% of people over 65 have some forms of hearing deficit, which can have devastating consequences on the quality of life. The objectives of the proposed programmatic research program is to take a bottom-up approach in using genetic mouse models of ARHL to determine the mechanisms and define therapeutic strategies for ARHL.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG051443-01A1
Application #
9151167
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (M2))
Program Officer
Wagster, Molly V
Project Start
2016-09-01
Project End
2021-05-31
Budget Start
2016-09-01
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$1,680,717
Indirect Cost
$289,526
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Shen, Haitao; Liu, Weilin; Geng, Qiaowei et al. (2018) Age-Dependent Up-Regulation of HCN Channels in Spiral Ganglion Neurons Coincide With Hearing Loss in Mice. Front Aging Neurosci 10:353
Zhang, Xiao-Dong; Coulibaly, Zana A; Chen, Wei Chun et al. (2018) Coupling of SK channels, L-type Ca2+ channels, and ryanodine receptors in cardiomyocytes. Sci Rep 8:4670
Sirish, Padmini; Ledford, Hannah A; Timofeyev, Valeriy et al. (2017) Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6. Circ Arrhythm Electrophysiol 10: