TMC1点突变引发渐进性耳聋的分子病理与细胞机制研究

耳蜗毛细胞为哺乳动物实现听觉机械电转导（MET）发生的细胞基础，TMC1作为与MET通道复合物高度相关的膜蛋白，已经被报道与很多类型的遗传性耳聋相关。通过患者家系研究与小鼠动物模型验证已知，TMC1的一些单碱基替换引发的单一氨基酸侧链的改变，可以引发渐进性的、非综合症式的遗传性耳聋。由于TMC1在耳蜗毛细胞中所承担的分子机制仍未完全被探明，因此对于此类遗传病所引发的渐进性耳聋依然缺乏可靠的临床治疗手段。在我们的研究中发现，TMC1在耳蜗毛细胞上介导了一种常开式漏电流，而这种漏电流的幅值与内、外毛细胞的发育与功能高度相关。同时，我们也观察到TMC1的M412K点突变能够在耳蜗毛细胞上介导显著增大的漏电流，而此时MET电流幅值并未显著变化。本项目旨在以TMC1点突变所引发的漏电流改变为切入点，探明TMC1经由漏电流幅值影响耳蜗毛细胞发育与生理功能维持的分子机制与细胞基础；同时研究不同背景电流

Mammalian auditory menchano-electrical transduction bases on cochlear hair cells. As a highly associated membrane protein, TMC1 has been reported in quiet a lot of research about hereditary hearing loss. Through the research of patient families and animal models, TMC1’s some single point nucleotide substitution have been confirmed leading to progressive genetic hearing loss. Due to the incomplete of TMC1’s cellular and molecular function study, there was not reliable therapeutic schedule for these progressive hearing loss. In our former reports, we found that TMC1 mediates a leak conductance in cochlear hair cells. And this background current is highly associated with development and cellular function of Inner and Outer hair cells. In our unpublished study, we found that a TMC1’s single point mutant M412K, also known as Beethoven version, will mediate significantly larger background conductance in cochlear hair cells. Meanwhile there would be no apparent change in MET amplitude. Our program aims on studying the mechanism of leak conductance increase caused by TMC1’s single residue substitution. Our study would present a novel model for hair cell development and function maintenance, also would explore therapeutic window for pharmacological or genetic therapy of such kind of progressive genetic hearing loss.