Ion Channel Function in Auditory and Vestibular Hair Cells

 描述(由申请人提供)：这些项目的长期目标是表征和鉴定内耳感觉信号的生理和分子基础。听觉器官和前庭器官都含有机械敏感的毛细胞，它们启动感觉信号；修改、调整和放大信号；然后将信号传输到第八脑神经的突触后神经元。了解这些感觉信号是如何产生、修改和传递的，对于设计未来内耳功能障碍的治疗方法是必要的。建议的研究集中在离子通道对毛细胞功能的贡献，并围绕两个特定的目标进行组织。1)我们的目标是更好地理解一种新形式的毛细胞机械敏感性，它存在于发育过程中的听觉毛细胞中。我们将从生物物理学、药理学和生理学的角度描述这种反应。我们将定位反应，包括最佳刺激部位和转导部位。我们将确定反应所需的基因和蛋白质，并将使用遗传、病毒和化学抑制来研究其功能。2)为了更完整地描述哺乳动物内耳的感觉适应，我们将研究听觉和前庭毛细胞的适应的功能和分子特性。由于这些器官探测的机械刺激具有非常不同的时间特征，我们假设听觉器官和前庭器官的毛细胞之间可能存在显著的生物物理和分子差异。我们将利用药理学、化学遗传学、病毒介导的基因敲除和靶基因的条件性遗传缺失来系统地研究这些毛细胞的感觉适应特性。从拟议的研究中得出的数据将为我们理解哺乳动物内耳中感觉信息的发展、产生和传输提供创新和重大的进展。

 DESCRIPTION (provided by applicant): The long term goal of these projects is to characterize and identify the physiological and molecular basis of sensory signaling in the inner ear. Both auditory and vestibular organs contain mechanosensitive hair cells that initiate the sensory signal; modify, tune and amplify the signal; and then transmit the signal to the postsynaptic neurons of the eighth cranial nerve. Understanding how these sensory signals are generated, modified and relayed is necessary to provide a foundation for design of future treatments for inner ear dysfunction. The proposed studies focus on ion channel contributions to hair cell function and are organized around two specific aims. 1) We aim to develop a better understanding of a novel form hair cell mechanosensitivity that is present in auditory hair cells during development. We will characterize the response biophysically, pharmacologically and physiologically. We will localize the response, both the site of optimal stimulation and the site o transduction. We will characterize the genes and proteins required for the response and we will use genetic, viral and chemical inhibition to investigate its function. 2) To provide a more complete description of sensory adaptation in the mammalian inner ear, we will investigate the functional and molecular properties of adaptation in auditory and vestibular hair cells. Because these organs detect mechanical stimuli with very different temporal characteristics, we hypothesize that there may be significant biophysical and molecular differences between hair cells of auditory and vestibular organs. We will use pharmacological, chemical-genetic, viral-mediated gene knockdown and conditional genetic deletion of target genes to systematically investigate the properties of sensory adaptation in these hair cells. The data that emerge from the proposed studies will provide innovative and significant advances in our understanding of the development, generation and transmission of sensory information in the mammalian inner ear.