GENETIC ANALYSIS OF MAMMALIAN HEARING SENSITIVITY

描述（由申请人提供）：哺乳动物耳蜗通过位于耳蜗外毛细胞（OHC）中的机械放大过程（称为耳蜗放大）以显著的灵敏度对声音刺激做出响应。跨膜电压驱动的OHC索马长度的变化（称为OHC电活动性）已被假设为提供机械反馈，从而耳蜗放大。OHC侧壁内的分子复合物（称为运动复合物）被认为是OHC电运动的原因。在这个建议中，我们专注于在小鼠的OHC电活动和耳蜗放大的机制的遗传分析。使用基因敲除小鼠，我们提供了证据表明，普雷斯廷，最近发现的运动复合体的质膜蛋白质，需要OHC电运动和耳蜗放大。为了进一步阐明OHC电活动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电活动是否是OHC中产生耳蜗放大的唯一活性机制。2. prestin介导的OHC电运动如何为耳蜗放大提供反馈;以及3. OHC外侧壁中运动复合体的其他分子如何促进prestin介导的OHC电运动，从而促进耳蜗放大。突变小鼠的生化、生理和遗传分析将使我们能够阐明OHC电活动和耳蜗放大的分子途径。我们的研究可能会提供深入了解的机制，听力损失涉及的缺陷，在OHC电活动发生在人类。

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.