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卓越的灵敏度、频率选择性和巨大的动态范围一直是听觉神经生物学的核心问题。两种相互竞争的机制被提出：哺乳动物特异性的基于pretin的外毛细胞（OHC）电运动性和普遍存在的立体纤毛运动性。在之前的资助期内，我们证明：(1)基于prestin的OHC电动力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及其向神经兴奋的传递中发挥了新的作用；(3)基于prestin的OHC电运动性似乎没有调整立体纤毛运动的作用点；(4)先前假设的OHC运动蛋白Glut5在OHC中检测不到，并且与耳蜗放大无关。基于这些和其他进展，我们提出了一个统一的放大机制，规定了调谐的立体纤毛运动和动力的电运动。然而，prestin是否同时发挥主动和被动的机械作用，以及基于prestin的电动力是否执行必要的循环反馈，仍然存在争议。此外，目前尚不清楚prestin如何驱动侧质膜和潜在的OHC电运动性细胞骨架结构的协调变化。为了进一步阐明prestin在OHC电运动性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prestin的OHC电运动性如何产生耳蜗放大。2）. 确定普司汀在ohc中的分布、运输和膜迁移率。最近，据报道，人类prestin基因的两个假定突变可导致耳聋。大剂量水杨酸钠（阿司匹林）引起的听力损失可归因于pretin基OHC电运动性的降低。此外，普司汀可能是一些高频听力损失患者听力损失的共同效应。我们的研究将有助于我们对耳蜗放大和各种遗传和环境因素引起的耳聋的病理生理的理解。

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.