Genetic analysis of mammalian hearing sensitivity

人类和其他哺乳动物的耳蜗会如何实现其非凡的敏感度， 频率选择性和巨大的动态范围一直是 听觉神经生物学。已经提出了两个相互竞争的机制： 哺乳动物特异的基于prestin的外毛细胞(OHC)的电动活动和 无处不在的立体纤毛运动。在上一个资助期，我们证明了：(1) 基于Prestin的OHC电动学对于耳蜗放大是必要的；(2)Prestin 在耳蜗被动机械反应的频率调谐方面起到了新的作用 它们传递给神经兴奋；(3)基于Prestin的OHC电活动不 出现调节立体纤毛运动的操作点；和(4)Glut5，以前的 假设的OHC马达蛋白，在OHC中检测不到，并且不有助于 耳蜗术后放大。基于这些和其他方面的进展，我们提出了一个统一的 规定用于调谐和电动的立体纤毛运动的放大机构 为了权力。然而，普雷斯汀是否既活跃又活跃，仍然存在争议。 被动的机械作用以及基于Prestin的电动是否执行 必要的逐周期反馈。此外，还不清楚Prestin是如何驱动的 侧质膜和下层细胞骨架的协调变化 用于OHC电动的结构。进一步阐明Prestin在OHC中的作用 电动和耳蜗放大，我们将追求以下具体目标：1) 确定基于prestin的OHC电动如何产生耳蜗放大。2)。 确定Prestin在毛细胞中的分布、运输和膜流动性。 最近，据报道，人类prestin基因的两个假定突变会导致 耳聋。大剂量水杨酸钠(阿司匹林)引起的听力损失已被证实 归因于基于prestin的OHC电动能力的降低。此外，预置很可能 高频听力损失患者中常见的听力损失效应。 我们的研究将极大地帮助我们理解耳蜗放大和 由多种遗传和环境因素引起的耳聋的病理生理学。

How the cochleae of humans and other mammals achieve their remarkable sensitivity, frequency selectivity, and enormous dynamic range has been the central question in auditory neurobiology. Two competing mechanisms have been proposed: the mammalian-specific prestin-based outer hair cell (OHC) electromotility and the ubiquitous stereociliary motility. In the previous funding period, we demonstrated that: (1) prestin-based OHC electromotility is necessary for cochlear amplification; (2) prestin plays a novel role in frequency tuning of cochlear passive mechanical responses and their transmission to neural excitation; (3) prestin based OHC electromotility does not appear to adjust the operating point of stereociliary motility; and (4) Glut5, a previously hypothesized OHC motor protein, is undetectable in OHCs and does not contribute to cochlear amplification. Based on these and other advances, we propose a unified amplificatory mechanism that stipulates stereociliary motility for tuning and electromotility for power. However, it remains controversial whether prestin plays both active and passive mechanical roles and whether prestin-based electromotility performs the necessary cycle-by-cycle feedback. Furthermore, it is still unclear how prestin drives coordinated changes in the lateral plasma membrane and underlying cytoskeletal structure for OHC electromotility. To further elucidate prestin's roles in OHC electromotility and cochlear amplification, we will pursue the following Specific Aims: 1) Determine how prestin-based OHC electromotility generates cochlear amplification. 2). Determine the distribution, trafficking, and membrane mobility of prestin in OHCs. Recently, two putative mutations in the human prestin gene have been reported to cause deafness. Hearing loss induced by large doses of sodium salicylate (aspirin) has been attributed to a reduction in prestin-based OHC electromotility. Moreover, prestin is likely the common effector of hearing loss in some patients with high-frequency hearing loss. Our studies will contribute greatly to our understanding of cochlear amplification and the pathophysiology of deafness caused by a variety of genetic and environmental factors.