Genetic analysis of mammalian hearing sensitivity

描述（由申请人提供）：人类和其他哺乳动物的耳蜗如何实现其显著的灵敏度、频率选择性和巨大的动态范围一直是听觉神经生物学的中心问题。两种竞争机制已被提出：前列腺特异性prestin为基础的外毛细胞（OHC）的电运动和无处不在的立体纤毛运动。在前期研究中，我们发现：（1）prestin介导的OHC电活动是耳蜗放大所必需的;（2）普雷斯廷在耳蜗被动机械反应的频率调谐及其向神经兴奋的传递中起着新的作用;（3）普雷斯廷介导的OHC电活动似乎并不调节立体纤毛运动的工作点;（4）Glut 5是一种先前假设的OHC运动蛋白，在OHC中检测不到，并且不有助于耳蜗放大。基于这些和其他进展，我们提出了一个统一的放大机制，规定立体纤毛运动的调谐和电动力。然而，普雷斯廷是否同时扮演主动和被动的机械角色，以及基于普雷斯汀的电运动是否执行必要的逐周期反馈，仍然存在争议。此外，目前还不清楚普雷斯廷如何驱动协调的变化，在侧质膜和底层的细胞骨架结构的OHC电运动。为了进一步阐明普雷斯廷在OHC电活动和耳蜗放大中的作用，我们将追求以下具体目标：1）确定基于普雷斯丁的OHC电活动如何产生耳蜗放大。2）。确定普雷斯廷在OHC中的分布、运输和膜流动性。最近，两个假定的人类普雷斯廷基因突变已被报道导致耳聋。大剂量水杨酸钠（阿司匹林）引起的听力损失归因于基于prestin的OHC电运动的减少。此外，普雷斯廷可能是一些高频听力损失患者听力损失的常见效应物。我们的研究将大大有助于我们理解耳蜗放大和耳聋的病理生理学引起的各种遗传和环境因素。 公共卫生相关性： 据估计，美国有2800万人是聋人或听力障碍者。大约有150万3岁或3岁以上的人双耳失聪，每1 000名活产婴儿中有2至3人患有先天性听力损失。在美国，超过4000万人遭受不同程度的噪声引起的听力损失。近一半的65岁以上的人患有与年龄相关的听力损失。尽管我们对这些听力障碍的理解取得了重大进展，但对疾病的原因和成人的正常听力过程知之甚少。在这里，我们打算研究普雷斯廷，一种内耳中的运动蛋白，对我们的听觉灵敏度和频率选择性至关重要。最近，两个假定的人类普雷斯廷基因突变已被报道导致耳聋。大剂量水杨酸钠（阿司匹林）引起的听力损失已被归因于prestin介导的听力障碍。此外，普雷斯廷可能是一些高频听力损失患者听力损失的常见效应物。我们的研究将极大地有助于我们理解耳蜗生理学和由各种遗传和环境因素引起的耳聋的病理生理学。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: An estimated 28 million people in the United States are deaf or hard of hearing. Approximately 1.5 million individuals aged 3 years or older are deaf in both ears and 2 to 3 per 1,000 live births suffer congenital hearing loss. More than 40 million persons in the United States suffer various levels of noise induced hearing loss. Nearly half of people over 65 years of age develop age-related hearing loss. Despite the significant progress in our understanding of these hearing disorders, very little is known about the disease causes and about the normal hearing processes in adults. Here we propose to study prestin, a motor protein in the inner ear that is crucial for our hearing sensitivity and frequency selectivity. 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 prestin-mediated hearing dysfunction. 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 physiology and the pathophysiology of deafness caused by a variety of genetic and environmental factors.