Gap Juncitional Function in Hearing

The long-term goal of this project is to investigate the function of connexins in hearing and the deafness mechanisms underlying connexin mutation-induced hearing loss. Connexin 26 (Cx26, GJB2) mutations account for >50% of cases of nonsyndromic hearing loss, ranging from profound congenital deafness at birth to mild, progressive late-onset hearing loss in late childhood. However, the underlying deafness mechanisms still remain largely undetermined. Lack of detailed information about deafness mechanisms directly hampers efforts to develop efficient and practicable therapeutic interventions. In particular, patients with progressive late-onset hearing loss are good candidates for applying protective and therapeutic interventions. Recently, we found that Cx26 deficiency induced congenital deafness is associated with cochlear developmental disorders rather than cell degeneration, whereas Cx26 deficiency induced late-onset hearing loss is associated with the reduction of active cochlear amplification by affecting outer hair cell electromotility, despite the lack of connexin expression in outer hair cells. We also found that the hypothesized defect of K+-recycling is not responsible for Cx26 deficiency induced hearing loss. Our working hypothesis in this project is that Cx26 deficiency induced hearing loss may have different deafness mechanisms: congenital deafness may result from cochlear developmental disorders, whereas late-onset hearing loss may result from the reduction of active cochlear amplification. Five specific aims (SAs) will be tested for this novel hypothesis. We will first investigate the mechanisms underlying Cx26 deficiency induced cochlear developmental disorders. Organ development relies on well-orchestrated intercellular communication to coordinate gene expression. Gene expression can be regulated by many factors at many stages, such as promoters, transcription factors, and small non-coding RNAs (miRNAs/siRNAs). However, none of these regulatory factors is intercellularly exchangeable through gap junctions except miRNAs/siRNAs. We will test whether miRNAs/siRNAs can pass through inner ear gap junctions and whether Cx26 deficiency can disrupt miRNA/siRNA intercellular communication in the cochlea to influence cochlear development (SA1-2). Then, we will investigate how Cx26 deficiency in the cochlear supporting cells reduces active cochlear amplification in late-onset hearing loss (SA3). In SA4-5, we will further characterize and compare changes in channel properties and functions associated with Cx26 R75W and M34T mutations, which cause congenital deafness and late-onset hearing loss, respectively, and create mutation knockin mice to identify pathological changes in the cochlea. Undoubtedly, this systematic study will reveal detailed molecular and cellular mechanisms underlying Cx26 deficiency induced hearing loss and will also provide invaluable information for developing new strategies for protecting against and treating this common nonsyndromic deafness.