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 #
2R01DC006483-06
Application #
7987417
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
2011-01-01
Budget End
2011-12-31
Support Year
6
Fiscal Year
2011
Total Cost
$342,787
Indirect Cost
Name
Emory University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Yuan, Yongyi; Gao, Xue; Huang, Bangqing et al. (2016) Phenotypic Heterogeneity in a DFNA20/26 family segregating a novel ACTG1 mutation. BMC Genet 17:33
Chang, Qing; Wang, Jianjun; Li, Qi et al. (2015) Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange-Nielsen deafness syndrome. EMBO Mol Med 7:1077-86
Chang, Qing; Tang, Wenxue; Kim, Yeunjung et al. (2015) Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing. Neurobiol Dis 73:418-27
Yu, Q; Wang, Y; Chang, Q et al. (2014) Virally expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice. Gene Ther 21:71-80
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
Angeli, Simon; Lin, Xi; Liu, Xue Zhong (2012) Genetics of hearing and deafness. Anat Rec (Hoboken) 295:1812-29
Yu, Qing; Chang, Qing; Liu, Xia et al. (2012) 7,8,3'-Trihydroxyflavone, a potent small molecule TrkB receptor agonist, protects spiral ganglion neurons from degeneration both in vitro and in vivo. Biochem Biophys Res Commun 422:387-92

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