Among many genes linked to deafness, mutations in connexin26 (Cx26) gene (GJB2) are the most common genetic defects found in children with autosomal recessive and dominant nonsyndromic hearing loss. Studies in many ethnic populations have linked Cx26 mutations to about one-half of patients with prelingual severe-to-profound nonsyndromic hearing loss. Screening for mutations in the Cx26 and Cx30 genes is now a routine genetic test offered by many medical centers in the United States and Europe. Since the role played by Cx26 in the cochlea is unclear, no mechanism-based therapeutic strategy exists for developing effective prevention and treatment today. ? ? The investigators' long-term goal is to understand the molecular mechanisms of gap junction (GJ) mediated functions in the mammalian cochlea and to explore mechanism-based molecular approaches to restore hearing in Cx26 and Cx30 mutant mouse models that are applicable to patients. Preliminary studies demonstrated that the hearing of deaf Cx30-/- mice was completely restored to normal by transgenically over-expressing Cx26 gene from a modified bacterial artificial chromosome (BAC) incorporated in the Cx30-/- mouse genome. These results indicated that heteromeric GJs consisting of Cx26 and Cx30 were not essential for normal hearing. Since amino acid sequences of Cx26 and Cx30 are 80% identical and they co-assemble to form heteromeric GJs in the cochlea, the preliminary data also raised the possibility that up-regulating the expression of Cx30 gene may restore hearing of conditional Cx26-/- mice as well. This application, in response to PA-06-342, is initiated to test this hypothesis. ? ? In contrast to introducing foreign DNA materials to correct the dysfunctional gene by traditional gene therapy approaches, the investigators' new idea relies on up-regulating the expression of a gene already exist in the genome of the Cx26-mutant mice or patients. Successful outcome of their experiments may form the basis for pursuing innovative and mechanism-based therapeutic strategy for preventing and/or treating patients suffering from Cx26 mutation-linked deafness. Investigations about the mechanisms up-regulating the Cx26 gene expressions and slowing down the degradation of Cx26 may become therapeutically relevant, therefore may lead to new research directions for studying the prevention and treatment of connexin-related deafness. ? ? ?
