Studies in cochlear hair cell transduction

描述(摘自申请者的摘要)：在哺乳动物中，外毛细胞 在耳蜗内提供局部放大，负责耳部的 显著的灵敏度和频率选择性。虽然美国政府对 哺乳动物耳蜗对局部、外毛细胞的扩增作用广泛 接受了，但对于扩大机制没有达成一致意见。一种观点是 在细胞感受器潜力的推动下，体细胞形状发生变化，称为 电动，提供机械反馈，从而放大。一个 另一种概念是，扩增是作为细胞的一个附件出现的 前置换能器突起，因此驻留在立体纤毛内。我们现在有了 确定了编码特殊运动蛋白(Prestin)的基因 产生电动。因此，现在可以测试这些替代方案。 我们将制作一种缺乏预蛋白的小鼠模型(基因敲除小鼠)，并测试其 听证。正常的听力会暗示第二种放大机制 是可操作的，而严重的听力损失将表明由于 失灵，听力下降。此外，广泛的 对Prestin本身的分子性质进行了实验 目的是产生各种抗体，以确定其拓扑结构和 它与已知影响外毛细胞的各种因素相互作用 能动性。

DESCRIPTION (Adapted from applicant's abstract): In mammals, outer hair cells provide local amplification in the cochlea that is responsible for the ear's remarkable sensitivity and frequency selectivity. While the reliance of the mammalian cochlea on local, outer hair cell based-based amplification is widely accepted, there is no agreement about the amplifying mechanism. One view is that, powered by the cell's receptor potential, somatic shape changes, called electromotility, provide mechanical feedback and thereby amplification. An alternative concept is that amplification arises as an adjunct to the cell's forward transducer process and thus resides in the sterocilia. We have now identified the gene that codes for the specialized motor protein (prestin) that produces electromotility. Thus, it is now possible to test these alternatives. We shall produce a mouse-model that lacks prestin (knockout mouse) and test its hearing. Normal hearing will imply that the second mechanism of amplification is operative, whereas significant hearing loss will show that due to the non-functional prestin, hearing has been degraded. In addition, extensive experiments are conducted on the molecular properties of prestin itself with aims of producing various antibodies against it, to determine its topology and its interaction with various agents that are known to influence outer hair cell motility.