The claudin family is composed of transmembrane proteins that are an essential part of the tight junctions forming barriers in epithelial and endothelial tissue. In the cochlea, Claudin 9 (Cldn9) is highly expressed in the tight junctions of the organ of Corti, where separation of high potassium (K+) endolymph from the low K+ perilymph fluid is necessary for protection of the outer hair cells (OHCs), as well as for maintaining the Endocochlear Potential (EP) (Nakano et al 2009, Wangemann and Schacht, 1996). Our lab has focused on identifying genes that are resistant to noise stress (Street, et al. 2014). Among the five quantitative trait loci (QTL) that appeared in the 129S6/SvEvTac (129S6) strain, the strongest QTL contains Cldn9. Surprisingly, when we started to study the noise sensitivity it became apparent that this locus also displayed an age-related hearing loss (AHL) phenotype that was non-progressive hearing loss (NPHL), and a significant mid-frequency ARHL by 12 months. To explore functional attributes of Cldn9, we have recently developed a Doxycyline (dox) regulated version of the Cldn9 gene that can be up or down regulated. We are assured that the changes that we observe after dox manipulation are due to the Cldn9 expression. Here we will examine the role of Cldn9 in an aging auditory system, including the influence noise and the question of Cldn9?s role in potassium leakage.

Public Health Relevance

We are studying the genetic mechanisms that contribute to hearing loss and deafness. Our goal is to identify potential targets for pharmacological or other therapies to treat hearing loss. Here we will investigate the role of Claudin 9 proteins in protection of the outer hair cells in the aging auditory system.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG051443-01A1
Application #
9151171
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (M2))
Project Start
2016-09-01
Project End
2021-05-31
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$386,231
Indirect Cost
$10,875
Name
University of Nevada Reno
Department
Type
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: