Mutations in connexin26 (Cx26) and Cx30 are the most common causes of hereditary deafness in humans. These mutations are one of the most frequently-observed human genetic defects, which are responsible for millions of prelingual severe hearing impairment cases. Although the causal effect of Cx mutations for congenital hearing loss is well established, little is known about mechanisms of hearing impairment caused by the Cx mutations. Currently no mechanism-based therapies are available for deaf patients suffering Cx mutations. Results obtained from last grant period demonstrated that loss-of-function Cx26 mutations arrest normal morphological development of the hearing organ (the organ of Corti), and suggested that a failure to develop endocochlear potential (the battery that powers the hearing transduction) causes deafness in Cx30 mutant mice. In this grant renewal we seek support to further investigate molecular mechanisms and explore novel therapeutic strategies for deafness caused by Cx26 and Cx30 mutations that are linked to human sensorineural hearing impairments. We will test the functional roles of Cx26 in the normal maturation of the organ of Corti. We will rescue hearing of Cx30 null mutant mice by a genetic approach to over-express the Kcnj10 gene that is known to be critical for the development of the normal endolymphatic potential. Results of these studies will have direct implications for human deafness caused by Cx mutations that are responsible for about half of non-syndromic congenital hearing loss cases.

Public Health Relevance

Mutations in connexin26 (Cx26) and Cx30 are the most common causes of hereditary deafness in humans. Although the causal effect of Cx mutations for congenital hearing loss is well established, little is known about mechanisms of hearing impairment caused by the Cx mutations and no mechanism-based therapies are available for deaf patients suffering Cx mutations currently. In this project we will investigate functional roles of Cx26 in the normal maturation of the hearing organ (the organ of Corti) and novel means to rescue hearing of Cx30 null mutant mice by a genetic approach.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC006483-09
Application #
8588909
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (02))
Program Officer
Watson, Bracie
Project Start
2004-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
9
Fiscal Year
2014
Total Cost
$308,509
Indirect Cost
$109,471
Name
Emory University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Yuan, Yongyi; Zhang, Jianguo; Chang, Qing et al. (2014) De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness-onychodystrophy syndrome. Cell Res 24:1370-3
Wang, Yunfeng; Sun, Yu; Chang, Qing et al. (2013) Early postnatal virus inoculation into the scala media achieved extensive expression of exogenous green fluorescent protein in the inner ear and preserved auditory brainstem response thresholds. J Gene Med 15:123-33
Lin, Lan; Wang, Yun-Feng; Wang, Shu-Yi et al. (2013) Ultrastructural pathological changes in the cochlear cells of connexin 26 conditional knockout mice. Mol Med Rep 8:1029-36
Yu, Qing; Chang, Qing; Liu, Xia et al. (2013) Protection of spiral ganglion neurons from degeneration using small-molecule TrkB receptor agonists. J Neurosci 33:13042-52
Qu, Yan; Tang, Wenxue; Zhou, Binfei et al. (2012) Early developmental expression of connexin26 in the cochlea contributes to its dominate functional role in the cochlear gap junctions. Biochem Biophys Res Commun 417:245-50
Tang, Wenxue; Qian, Dong; Ahmad, Shoeb et al. (2012) A low-cost exon capture method suitable for large-scale screening of genetic deafness by the massively-parallel sequencing approach. Genet Test Mol Biomarkers 16:536-42
Lin, Xi (2011) Perception of sound and gravity by TMC1 and TMC2. J Clin Invest 121:4633-6
Wang, Yunfeng; Chang, Qing; Tang, Wenxue et al. (2009) Targeted connexin26 ablation arrests postnatal development of the organ of Corti. Biochem Biophys Res Commun 385:33-7
Sun, Yu; Tang, Wenxue; Chang, Qing et al. (2009) Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea. J Comp Neurol 516:569-79

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