The components of the mechanotransduction (MET) channel in the hair cells of the cochlea are still unknown. However, the characteristics of the MET channel and knowledge about mechanosensation are known and are consistent with members of the TRP family of ion channels. Because the polycystic kidney disease (Pkd1) gene plays a role in fluid sensation and Ca2+ ion uptake in kidney cilia and is a member of the TRP family, which is known to form cation channels with conduction similar to that of MET channels, we propose that Pkd1 could be part of the MET channel in the hair cells of the cochlea. Using two mutant mouse models with two independent alleles of Pkd1, we plan to characterize the role of Pkd1 in the cochlea and more specifically the MET channel (Aims 1 and 2). We have shown that there is a localization of Pkd1 mRNA in hair cells and localization of protein to the hair bundles of the cochlea. In addition, a Pkd1T3041V mutant mouse have an average 25 dB hearing loss and abnormal hair bundle morphology (preliminary results). In addition, a hair cell-specific conditonal knockout allele shows an average 30 dB hearing loss and abnormal hair bundle morphology (preliminary results). Through further analysis of the Pkd1T3041V allele and the hair cell-specific knockout allele of Pkd1, we plan to test the hypothesis that Pkd1 is a component of the MET channel in the hair cells and provide in vivo evidence of the roles of Pkd1 in the inner ear. Our studies of the manifestations and pathology of these interactions should yield targets for the prevention and treatment of human PKD1 disease in both the ear and the kidney. ? ? ?
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