Inner ear ion channels in healthy and diseased conditions

摘要： 以前的研究已经证明，这种精致的敏感性和 耳蜗肌的频率选择性部分依赖于电压依赖的毛束运动和外毛细胞 (OHC)侧壁电动(Em)。几种与耳蜗声放大有关的基因产物 已经被发现，它们的突变已经被证明在人类和小鼠模型中导致听力损失。 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) 导致严重的进行性听力损失(PHL：DFNA2)。而全球范围内患有DFNA2的家庭 尽管已经确定，但该病的发病机制在很大程度上尚不清楚。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(螺旋状)传递到大脑 神经节神经元(SGN)。这些特征使得分离和确定其功能是不切实际的 属性。 我们假设，在OHC中Kv7.4电流的特性是通过Kv7.4与 KCNE4、钙结合蛋白2(CaBP2)及其形成簇的能力。第一次，我们有了 开发了创新和艰苦的策略，允许对II型听神经元进行强有力的评估 功能。 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，以揭示II型SGN/OHC生理学的基本和新的可及领域。目标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 毛囊虫。在目标2中，我们将确定KCNE4和CaBP2在内耳中的体内功能。最后，在目标3中 我们将确定II型神经元对毛细胞的调节机制。 拟议的研究将揭示OHC功能的关键缺失环节，并首次确定 支配毛细胞的稀有的II型SGN的特征：因此，将盛行的I型SGN 以SGN为中心的生理学(已知)到全面理解不同的传入听觉神经元， 对治疗感音神经性耳聋(SNHL)至关重要的信息。

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).