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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：
10745190
负责人：
EBENEZER N YAMOAH
金额：
$ 50.4万
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 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10745190
关键词：
Acoustics Action Potentials Adult Afferent Neurons Aging Anatomy Auditory Axon Biological Assay Brain Brain Stem Clinical Cochlea Cochlear nucleus Code Complex Computer Models Confocal Microscopy Dependence Diameter Discrimination Disease Electrophysiology (science)Ensure Etiology Failure Frequencies Generations Genetic Models Geometry Grant Hair Cells Hearing Human Immunoelectron Microscopy Immunofluorescence Immunologic Ion Channel Kinetics Knock-in Knockout Mice Labyrinth Ligation Membrane Methods Microscopy Modification Mus Neurites Neurons Nodal Outcome Study Peripheral Phase Physiology Preparation Property Resolution Role SCN8A gene Sensory Shapes Sound Localization Source Speech Speed Stimulus Testing Work auditory pathway computer studies detector electric impedance hearing impairment hearing loss treatment hidden hearing loss in vivo innovation interdisciplinary approach live cell imaging loss of function meter millisecond mouse model myelination neural neuromechanism neuronal cell body new therapeutic target novel therapeutics optogenetics patch clamp pharmacologic prevent protein protein interaction response signal processing sound sound frequency spiral ganglion stem superresolution imaging superresolution microscopy temporal measurement treatment strategy voltage

项目摘要

Primary auditory afferent neurons conduct sound-evoked action potentials (APs) through surprisingly small- diameter axons at remarkable speed and with millisecond precision. The response properties of the auditory neuron (AN) are phased-locked for low-frequency (<5 kHz) sounds, suggesting that conduction failure is a rarity. However, the neural mechanisms that enable swift and phase-locked conduction are poorly understood. We hypothesize that ANs utilize non-uniform nodal, internodal, and patchy nodal ionic channel distribution to maintain fast conduction velocity (CV). These features optimize action potential (AP) CV and prevent AP conduction failure despite the structural limitations of the AN. We propose to test the underlying hypotheses using various knockin and knockout mouse models and pharmacological strategies. We utilize innovations such as optogenetics, high-resolution microscopy, and multiple electrophysiological approaches. We aim to determine 1) AN axonal ion channels' expression, colocalization, and interactions. We will employ multidisciplinary approaches to assess the expression distribution of specific ionic channels in AN axons. 2) The functional and physical interactions between specific ionic channels in AN neurites. The proximity of certain channels shapes the APs of ANs for high-speed conduction. We will use proximity ligation assay (PLA), live-cell imaging, and spatial and temporal resolution recordings to quantify the protein-protein interactions. 3) Axonal ionic channels' ex vivo and in vivo functional roles of ion channels that shape AN AP CV will be examined. We will use patch-clamp analyses of the kinetics, voltage dependence, and conductance in AN neurons to determine the underlying mechanisms for the differences in response properties and CV using computational studies. Thus, we will address the complexity of anatomic projections and signal processing and subsequent alterations of the structural and ionic conductances that would alter AP CV. This information is a necessary step toward developing treatments for hearing loss.

初级听觉传入神经元通过令人惊讶的小- 以惊人的速度和毫秒级的精确度制造直径的轴突。听觉的反应特性神经元（AN）对于低频（<5 kHz）声音是锁相的，这表明传导失败是罕见的。然而，使快速和锁相传导的神经机制知之甚少。我们假设AN利用不均匀的结、结间和斑片状结离子通道分布以维持快速传导速度（CV）。这些功能可优化动作电位（AP）CV并防止AP 尽管AN的结构限制，但传导失败。我们建议使用各种敲入和敲除小鼠模型来测试潜在的假设，药理学策略我们利用光遗传学、高分辨率显微镜和多种电生理方法。我们的目的是确定1）AN轴突离子通道的表达，共定位，和相互作用。我们会委聘多学科方法来评估特定离子通道在AN轴突中的表达分布。2)的 AN神经突中特定离子通道之间的功能和物理相互作用。某些人的接近通道塑造AN的AP以实现高速传导。我们将使用邻位连接测定（PLA），活细胞成像以及空间和时间分辨率记录以量化蛋白质-蛋白质相互作用。3)轴突离子通道的离体和体内功能作用的离子通道形状AN AP CV将被检查。我们将使用膜片钳分析的动力学，电压依赖性，和电导在AN神经元，以确定使用计算研究的响应特性和CV的差异的潜在机制。因此，我们将解决解剖投影和信号处理的复杂性以及随后的问题。结构和离子电导的改变将改变AP CV。这些信息是必要的步骤致力于开发听力损失的治疗方法。