Inner ear ion channels in healthy and diseased conditions

摘要： 先前的研究已经证明，敏感性的潜在机制， 耳蜗的频率选择性部分依赖于电压依赖性毛束运动和外毛细胞 (OHC)侧壁电活动性（eM）。参与耳蜗声音放大的几种基因产物， 已被鉴定，其突变已被证明会导致人类和小鼠模型的听力损失。 例如，K+通道（Kv）的突变，如Kv7.4（在控制OHC膜兴奋性方面至关重要） 导致深度进行性听力损失（PHL：DFNA 2）。虽然全球范围内的DFNA 2家庭 虽然已经确定，但疾病的机制在很大程度上是未知的。此外，OHC的活动是 通过稀少的（~5%）和小直径的无髓鞘II型听觉神经元（螺旋神经元）传递到大脑 神经节神经元（SGN）。这些特征使得分离和确定它们的功能变得不切实际。 特性. 我们假设OHC中Kv7.4电流的性质是通过Kv7.4与 KCNE 4、Ca 2+结合蛋白2（CaBP 2）及其形成簇的能力。这是我们第一次 开发了创新和艰苦的战略，允许强大的评估II型听觉神经元 功能协调发展的 我们将部署创新的分子生物学、电生理学、成像技术和基因靶向 小鼠模型，以阐明II型SGN/OHC生理学的基本和新的可及竞技场。要求1 将确定Kv7.4电流独特的低电压激活特性的分子决定因素， OHC。在目标2中，我们将确定KCNE 4和CaBP 2在内耳中的体内功能。最后，在Aim 3中 我们将确定OHC的II型神经元调节的潜在机制。 拟议的研究将揭示OHC功能的关键缺失环节，并首次确定 稀少的II型SGN的特征支配OHC：因此，改变了流行的单一I型SGN， SGN为中心的生理学（这是已知的），以全面了解不同的传入听觉神经元， 感音神经性听力损失（SNHL）的治疗

Abstract: Previous studies have demonstrated that the mechanisms underlying the exquisite sensitivity and frequency selectivity of the cochlea rely partly on the voltage-dependent hair bundle motility and outer hair cell (OHC) lateral wall electromotility (eM). Several gene products involved in cochlear sound amplification have been identified, and their mutations have been shown to result in hearing loss in human and mouse models. For example, mutations of K+ channels (Kv), such as Kv7.4 (critical in controlling OHC membrane excitability) result in profound progressive hearing loss (PHL: DFNA2). While the global expanse of families with DFNA2 has been identified, the mechanism of the disease is largely unknown. Additionally, the activity of OHCs is transmitted to the brain via the scarce (~5%) and small diameter, unmyelinated type II auditory neurons (spiral ganglion neurons (SGNs). These features have made it impractical to isolate and to determine their functional properties. We hypothesize that the properties of Kv7.4 currents in OHCs are achieved by the interaction of Kv7.4 with KCNE4, the Ca2+ binding protein 2 (CaBP2) and their ability to form clusters. For the first time, we have developed innovative and painstaking strategies that allow robust assessment of type II auditory neuron functions. We will deploy innovative molecular biology, electrophysiology, imaging techniques, and gene-targeted mouse models to unravel the fundamental and newly accessible arena of type II SGN/OHC physiology. Aim 1 will identify the molecular determinants for the unique low-voltage-activation properties of Kv7.4 currents in OHCs. In Aim 2 we will determine the in vivo functions of KCNE4 and CaBP2 in the inner ear. Finally, in Aim 3 we will identify the mechanisms underlying type II neuronal modulation of OHCs. The proposed studies will reveal critical missing links of OHC functions and for the first time, determine features of the scarce type II SGNs that innervate OHCs: therefore, shifting the prevailing monolithic type I SGN-centric physiology (that is known) to comprehensive understanding of distinct afferent auditory neurons, information essential for the treatment of sensorineural hearing loss (SNHL).