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.
| Cox, Brandon C; Chai, Renjie; Lenoir, Anne et al. (2014) Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development 141:816-29 |
| Liu, Zhiyong; Walters, Brandon J; Owen, Thomas et al. (2012) Regulation of p27Kip1 by Sox2 maintains quiescence of inner pillar cells in the murine auditory sensory epithelium. J Neurosci 32:10530-40 |
| Steigelman, Katherine A; Lelli, Andrea; Wu, Xudong et al. (2011) Polycystin-1 is required for stereocilia structure but not for mechanotransduction in inner ear hair cells. J Neurosci 31:12241-50 |
| Wu, Xudong; Steigelman, Katherine A; Bonten, Erik et al. (2010) Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1-deficient mice. Biochim Biophys Acta 1802:259-68 |
