GENETIC ANALYSIS OF MAMMALIAN HEARING SENSITIVITY

描述（由申请人提供）：哺乳动物耳蜗通过存在于耳蜗外毛细胞（ohc）中的机械放大过程（称为耳蜗放大）对声音刺激具有显著的敏感性。由跨膜电压驱动的OHC体长度变化（称为OHC电运动性）已被假设提供机械反馈，从而引起耳蜗放大。OHC外侧壁内的分子复合物（称为运动复合物）被认为是OHC电运动性的原因。在本研究中，我们着重对小鼠耳蜗OHC电运动性和耳蜗放大的遗传机制进行了分析。通过基因敲除小鼠，我们提供了证据，证明prestin（一种在运动复合体质膜上最近发现的蛋白质）是OHC电运动性和耳蜗放大所必需的。为了进一步阐明OHC电运动性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电运动性是否是OHC产生耳蜗放大的唯一有效机制。2. prestin介导的OHC电运动性如何为耳蜗放大提供反馈；和3。OHC外侧壁运动复合物的其他分子如何参与prepresin介导的OHC电运动性，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电运动性和耳蜗放大的分子途径。我们的研究可能为人类OHC电运动性缺陷引起的听力损失的机制提供见解。

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.