R01DC019687

Connexin Function and Mechanisms of CX26 Deficiency-Induced Hearing Loss - Summary

Mutations of the gap junction gene CX26 (GJB2) cause the most cases of hereditary deafness, ranging from profound congenital deafness at birth to mild late-onset hearing loss in childhood. Mouse models have shown that CX26 deficiency can induce cochlear developmental disorders, hair cell degeneration, reduction of the endocochlear potential (EP), and declining active cochlear amplification.

Further research has revealed that the cochlear developmental disorder, rather than hair cell degeneration, is the primary cause of congenital deafness. Late-onset hearing loss is associated with a reduction of outer hair cell (OHC) electromotility, even when hair cells have no connexin expression. Additionally, it has been found that the K+-recycling hypothesis is not the mechanism of deafness caused by CX26 deficiency. However, the detailed mechanisms of these pathological changes induced by CX26 deficiency remain unclear, and little is known about the pathological changes in the human cochlea.

Recently, gene therapy with viral expression of CX26 in the cochlea failed to restore hearing. The main reason for this failure is the lack of required knowledge about CX26 function in the cochlea and the mechanisms of deafness caused by CX26 deficiency. In this proposal, we aim to investigate CX26 function and the cellular and molecular mechanisms of CX26 deficiency-induced congenital deafness and late-onset hearing loss.

CX26 deficiency causes cochlear developmental disorders, indicating that gap junction (GJ) channels, as intercellular communication conduits, are crucial for cochlear development. Many factors, such as promoters, transcription factors, and miRNAs, can regulate gene expressions during development. However, none of these regulators are permeable to GJ channels except miRNAs. MiRNAs can regulate gene expression broadly and have a critical role in 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, thereby affecting cochlear development in congenital deafness.

Secondly, we will define how CX26 deficiency declines OHC electromotility, leading to late-onset hearing loss. This information will help identify patients who are good candidates for preventive and therapeutic interventions due to normal hearing earlier in life.

Recently, connexin non-channel function has 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 a backward-mutation screening approach to screen CX26 mutations in archival human temporal bones from patients with nonsyndromic hearing loss, whose pathological changes in the cochlea have been diagnosed. This will help identify mutation-induced pathological changes in the human cochlea.

These studies will reveal detailed deafness mechanisms caused by CX26 deficiency, providing urgently required information for developing efficient therapies.

Yale Univ

NOT APPLICABLE

93.173 - Research Related to Deafness and Communication Disorders

National Institute on Deafness and Other Communication Disorders (NIDCD) [HHS - NIH]

New Haven, Connecticut 065103218 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 05/31/26 to 05/31/27 and the total obligations have increased 503% from $504,146 to $3,037,536.