GENETIC ANALYSIS OF MAMMALIAN HEARING SENSITIVITY

描述(申请人提供)：哺乳动物耳蜗会通过位于耳蜗外毛细胞的机械放大过程(称为耳蜗放大)，对声音刺激做出非常敏感的反应。由跨膜电压(称为OHC电动)驱动的OHC胞体长度的变化被认为是为了提供机械反馈，从而提供耳蜗放大。OHC侧壁中的一个分子复合体(称为马达复合体)被认为是OHC电动的原因。在这项建议中，我们将重点放在OHC电动和耳蜗放大小鼠机制的遗传分析上。利用一只基因敲除的小鼠，我们提供了证据表明，Prestin是最近在运动复合体的质膜中发现的一种蛋白质，是OHC电动和耳蜗放大所必需的。为了进一步阐明OHC电动学的分子基础及其在耳蜗放大中的作用，我们计划确定：1.Prestin介导的OHC电动学是否是OHC产生耳蜗放大的唯一活跃机制。2.prestin介导的OHC电活动如何为耳蜗放大提供反馈；3.OHC侧壁运动复合体中的其他分子如何对prestin介导的OHC电活动作出贡献，从而促进耳蜗术后的放大。对突变小鼠的生化、生理和遗传分析将使我们能够阐明OHC电动和耳蜗放大的分子途径。我们的研究可能会为人类发生与OHC电动功能缺陷有关的听力损失的机制提供洞察力。

DESCRIPTION (provided by applicant): The mammalian cochlea responds to sound stimuli with remarkable sensitivity by a mechanical amplification process (termed cochlear amplification) that resides in the cochlea's outer hair cells (OHCs). The change of OHC soma length driven by transmembrane voltage (termed OHC electromotility) has been hypothesized to provide mechanical feedback and, thereby, cochlear amplification. A complex of molecules within the lateral wall of OHCs (termed the motor complex) is thought to be responsible for OHC electromotility. In this proposal, we focus on the genetic analysis of the mechanism underlying OHC electromotility and cochlear amplification in mice. Using a knockout mouse, we have provided evidence that prestin, a recently discovered protein in the plasma membrane of the motor complex, is required for OHC electromotility and cochlear amplification. To further elucidate the molecular basis of OHC electromotility and its role in cochlear amplification, we plan to determine: 1. whether prestin-mediated OHC electromotility is the only active mechanism in OHCs to generate cochlear amplification. 2. how prestin-mediated OHC electromotility provides feedback for cochlear amplification; and 3. how other molecules of the motor complex in the OHC's lateral wall contribute to prestin-mediated OHC electromotility and, thereby, cochlear amplification. Biochemical, physiologic, and genetic analyses of mutant mice will enable us to elucidate the molecular pathway that underlies OHC electromotility and cochlear amplification. Our studies may provide insights into the mechanisms by which hearing loss involving deficiencies in OHC electromotility occurs in humans.