Inner ear ion channels in healthy and diseased conditions

健康和患病条件下的内耳离子通道

• 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
• 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

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，精致灵敏度和 耳蜗的频率选择性部分依赖于电压依赖的头发束运动和外发池 （OHC）侧壁电动性（EM）。几种参与人工耳蜗扩增的基因产品具有 已被鉴定出来，它们的突变已被证明会导致人类和小鼠模型的听力丧失。 例如，K+通道的突变（KV），例如KV7.4（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）。而dfna2的全球家庭全球广阔 已经鉴定出来，该疾病的机制在很大程度上尚不清楚。此外，OHC的活动是 通过稀缺（〜5％）和小直径，无髓的II型听觉神经元（螺旋）传播到大脑 神经神经元（SGNS）。这些功能使分离和确定其功能是不切实际的 特性。 我们假设OHC中KV7.4电流的性能是通过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 制定了创新和艰苦的策略，可以对II型听觉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，成像技术和靶向基因 鼠标模型揭示了II型SGN/OHC生理学的基本和新近获得的领域。目标1 将确定KV7.4电流独特的低压激活特性的分子决定因素 OHCS。在AIM 2中，我们将确定内耳中KCNE4和CABP2的体内功能。最后，在目标3中 我们将确定OHC的II型神经元调制的基础机制。 拟议的研究将揭示OHC功能的关键缺失联系，并首次确定 稀缺的II型SGN的特征：因此，移动现行的单片I型 以SGN为中心的生理学（已知），以全面了解不同的传入听觉神经元， 治疗感官听力损失（SNHL）必不可少的信息。