Genetic analysis of mammalian hearing sensitivity

描述(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敏感性、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。已经提出了两种相互竞争的机制：哺乳动物特有的基于prestin的外毛细胞(OHC)电运动和无所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电动学对于耳蜗的放大是必需的；(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电动学似乎并不调节立体纤毛运动的工作点；以及(4)Glut5，一个先前假设的OHC马达蛋白，在OHC中不被检测到，并且对耳蜗管的放大没有贡献。在这些和其他进展的基础上，我们提出了一个统一的放大机制，规定了立体纤毛运动用于调谐，电动用于功率。然而，Prestin是否同时扮演着主动和被动的机械角色，以及Prestin的电动是否执行必要的逐个周期的反馈，仍然存在争议。此外，还不清楚prestin如何驱动OHC电动的侧质膜和潜在细胞骨架结构的协调变化。为了进一步阐明prestin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prestin的OHC电活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)引起的听力损失被归因于以Prestin为基础的OHC电动活动的减少。此外，在一些高频听力损失的患者中，Prestin可能是听力损失的常见影响因素。我们的研究将有助于我们更好地理解耳蜗放大和各种遗传和环境因素引起的耳聋的病理生理学。 公共卫生相关性： 据估计，美国有2800万人是聋人或重听人。大约有150万3岁或以上的人双耳失聪，每1000名活产儿中就有2到3人患有先天性听力损失。美国有4000多万人遭受不同程度的噪音导致的听力损失。65岁以上的人中有近一半会患上与年龄相关的听力损失。尽管我们对这些听力障碍的了解取得了重大进展，但人们对这些疾病的病因和成年人的正常听力过程知之甚少。在这里，我们建议研究prestin，这是内耳中的一种运动蛋白，对我们的听力敏感度和频率选择性至关重要。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)引起的听力损失被认为是由prestin介导的听力障碍所致。此外，在一些高频听力损失的患者中，Prestin可能是听力损失的常见影响因素。我们的研究将有助于我们更好地了解耳蜗生理学以及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.