Inner ear ion channels in healthy and diseased conditions

健康和患病条件下的内耳离子通道

基本信息

批准号：
10194449
负责人：
EBENEZER N YAMOAH
金额：
$ 52.01万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194449
关键词：
Address Adult Apoptotic Auditory Binding Proteins Biochemical Biological Brain Caliber Cell Death Cell membrane Cell physiology Cells Characteristics Cochlea Cochlear Implants Coupled Disease Electrophysiology (science)Ensure Family Frequencies Functional Imaging Funding Gene Targeting Grant Hair Hair Cells Hearing Image Imaging Techniques In Vitro Ion Channel Knowledge Laboratories Labyrinth Lateral Link Mediating Membrane Membrane Potentials Methods Molecular Molecular Biology Motivation Mutation Neurons Outer Hair Cells Performance Phenotype Physiology Potassium Channel Property Research Design Resistance Rest Role Sensorineural Hearing Loss Sensory Synapses Techniques Testing Time Transgenic Mice Voltage-Gated Potassium Channel Work cell motility cell type experimental study gene product hearing impairment human model improved in vivo inner ear diseases innovation insight mouse model null mutation peripherin progressive hearing loss protein complex sound spiral ganglion stem voltage

项目摘要

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).

抽象的：先前的研究表明，精致的敏感性和潜在的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）侧壁电动性（eM）。一些与耳蜗声音放大有关的基因产物已被鉴定，并且它们的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，例如 Kv7.4（对于控制 OHC 膜兴奋性至关重要）导致严重的进行性听力损失（PHL：DFNA2）。虽然全球范围内有大量患有 DFNA2 的家庭虽然已经确定，但该疾病的发病机制在很大程度上尚不清楚。此外，OHC 的活性是通过稀缺（~5%）且直径小、无髓鞘的 II 型听觉神经元（螺旋神经节神经元（SGN）。这些特征使得隔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 电流的特性是通过 Kv7.4 与 KCNE4、Ca2+ 结合蛋白 2 (CaBP2) 及其形成簇的能力。我们第一次有开发了创新和艰苦的策略，可以对 II 型听觉神经元进行稳健的评估功能。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技术小鼠模型揭示了 II 型 SGN/OHC 生理学的基本和新近领域。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 OHC。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 OHC 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，并首次确定支配 OHC 的稀有 II 型 SGN 的特征：因此，改变了普遍存在的整体 I 型以 SGN 为中心的生理学（已知）全面了解不同的传入听觉神经元，对于治疗感音神经性听力损失 (SNHL) 至关重要的信息。