# Connexin Function and Mechanisms of Cx26 Deficiency Induced Hearing Loss

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $504,146

## Abstract

Summary
 Mutations of gap junction gene Cx26 (GJB2) cause the most of hereditary deafness, ranging from profound
congenital deafness at birth to mild late-onset hearing loss in childhood. Mouse models show that Cx26
deficiency can induce cochlear developmental disorders, hair cell degeneration, endocochlear potential (EP)
reduction, and active cochlear amplification declining. We further found that the cochlear developmental
disorder rather than hair cell degeneration is a primary cause for congenital deafness, whereas late-onset
hearing loss is associated with reduction of outer hair cell (OHC) electromotility even hair cells have no
connexin expression. We also evidenced that K+-recycling hypothesis is not the deafness mechanism of Cx26
deficiency. However, detailed mechanisms of these pathological changes induced by Cx26 deficiency remain
unclear. Moreover, little is known about pathological changes in the human cochlea. Recently, gene therapy
with viral-expression of Cx26 in the cochlea was failed to restore hearing. The main reason is lack of required
knowledge of Cx26 function in the cochlea and deafness mechanisms by Cx26 deficiency.
 In this proposal, we will continually investigate Cx26 function and cellular and molecular mechanisms of
Cx26 deficiency-induced congenital deafness and late-onset hearing loss. Cx26 deficiency causes the
cochlear developmental disorder, indicating that gap junction (GJ) channels as an intercellular communication
conduit are crucial for the cochlear development. Many factors, such as promoters, transcription factors, and
miRNAs, can regulate gene expressions during development. However, none of these regulators is permeable
to GJ channels except miRNAs. miRNAs can regulate gene expression broadly and have a critical role in the
organ development. Deficiency of miRNAs can cause cochlear developmental disorders. In this study, we will
first test whether Cx26 deficiency can disrupt miRNA expression and intercellular communication in the
cochlea to affect cochlear development in the congenital deafness. Secondly, we will define how Cx26
deficiency decline OHC electromotility leading to late-onset hearing loss, which patients are good candidates
for administration of preventive and therapeutic interventions due to normal hearing in their earlier life.
Recently, connexin non-channel function has been emerged. Besides forming GJ channels, connexins can
participate in cell cytoskeleton formation. We will test whether Cx26 deficiency can impair cytoskeleton
formation in the OHC’s supporting cells, thereby changing OHC-loading (membrane tension) and declining
OHC electromotility and active cochlear amplification. Finally, we will use backward-mutation screening
approach to screen Cx26 mutations in the archival human temporal bones from patients with nonsyndromic
hearing loss, whose pathological changes in the cochlea have been diagnosed, to identify mutation-induced
pathological changes in the human cochlea. Apparently...

## Key facts

- **NIH application ID:** 10278375
- **Project number:** 1R01DC019687-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Hong-Bo Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $504,146
- **Award type:** 1
- **Project period:** 2021-07-19 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10278375

## Citation

> US National Institutes of Health, RePORTER application 10278375, Connexin Function and Mechanisms of Cx26 Deficiency Induced Hearing Loss (1R01DC019687-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10278375. Licensed CC0.

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