Mechanisms of hypersensitivity to sound-induced cochlear damage

对声音引起的耳蜗损伤过敏的机制

基本信息

批准号：
9764613
负责人：
Maria Eulalia Rubio
金额：
$ 60.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764613
关键词：
AMPA Receptors Acoustics Address Age-Months Aging Androgens Attention Biochemical Biological Factors Ca(2+)-Transporting ATPase Castration Cochlea Cochlear Nerve Complex Confocal Microscopy Data Endoplasmic Reticulum Environment Estradiol Estrogen Receptors Estrogens Exhibits Female Fiber Frequencies Glutamate Receptor Glutamates Gonadal Hormones Gonadal Steroid Hormones Hearing Hormones Hour Human Hypersensitivity Immunohistochemistry Inner Hair Cells Ischemia Knock-out Knockout Mice Labyrinth Lead Link Measures Mediating Molecular Mus Neurons Noise Ovarian Ovarian hormone Pathogenesis Phosphorylation Positioning Attribute Process Publishing Pump Quantitative Reverse Transcriptase PCR Role Sensory Sex Differences Signal Transduction Structure Surface Swelling Synapses Synaptic Transmission System Testing Western Blotting auditory pathway base childhood hearing loss excitotoxicity hearing impairment male mutant nerve supply neurotoxicity postsynaptic protective effect receptor receptor function ribbon synapse sexual dimorphism sound spiral ganglion trafficking transmission process

项目摘要

Project Summary All information about the acoustic environment is carried from the inner ear to the CNS by the afferent fibers of the cochlear nerve. Rapidly gating AMPA glutamate receptors (AMPAR; GluA2, GluA3 and GluA4 subunits) mediate synaptic transmission at the mature synapse between the inner hair cells (IHC) and the afferent fibers of the cochlear nerve (IHC synapse). However, the contribution of each type of AMPAR subunit to overall glutamatergic receptor function and afferent transmission/sensitivity in the cochlea is poorly understood. Understanding this process is important because glutamate excitotoxicity through AMPAR has been implicated in the pathogenesis of hearing loss caused by noise, ischemia and aging. Sex differences in the vulnerability to hearing loss occur in humans. We therefore began investigating the contribution of AMPAR subunits to transmission at the IHC synapse and whether there are sex-specific differences in AMPAR subunits that contribute to sound-induced cochlear damage and hearing loss. Based on functional and ultrastructural preliminary data, we now hypothesize that “GluA3 AMPAR subunits have a critical role in the sexually dimorphic vulnerability to hearing loss”. To define mechanistically how GluA3 contributes to the structural and molecular components of IHC synapses and to sex differences that underlie the hypersensitivity to sound- induced cochlear damage, we will use a powerful combination of functional (ABRs, DPOAEs), immunocytochemical (confocal microscopy), biochemical, qRT-PCR, and ultrastructural approaches to test the following hypotheses. In Aim 1, we will determine whether GluA3 promotes the abundance of GluA2 at IHC synapses. In Aim 2, we will determine whether GluA3 at IHC synapses protects mice from sound-induced cochlear damage. Aim 3, based on published data and our preliminary findings, we propose the hypothesis that in the absence of GluA3, ovarian hormones facilitate the hypersensitivity to sound-induced cochlear damage, while androgens have protective effects. These proposed studies are the first to address the important question of how changes in AMPAR subunit composition lead to sex differences in hearing loss.

项目概要有关声环境的所有信息均由内耳的传入纤维从内耳传送到中枢神经系统。耳蜗神经快速门控 AMPA 谷氨酸受体（AMPAR；GluA2、GluA3 和 GluA4 亚基）介导内毛细胞 (IHC) 和传入纤维之间成熟突触的突触传递然而，每种类型的 AMPAR 亚基对整体的贡献。耳蜗中谷氨酸能受体的功能和传入传输/敏感性知之甚少。了解这个过程很重要，因为 AMPAR 引起的谷氨酸兴奋毒性已被牵涉其中在噪音、缺血和衰老引起的听力损失的发病机制中，性别差异易受影响。因此，我们开始研究 AMPAR 亚基对人类听力损失的影响。 IHC 突触的传递以及 AMPAR 亚基是否存在性别特异性差异基于功能和超微结构，导致声音引起的耳蜗损伤和听力损失。初步数据显示，我们现在发现“GluA3 AMPAR 亚基在性行为中具有关键作用” 听力损失的二态性脆弱性”从机械上定义 GluA3 如何对结构和听力损失做出贡献。 IHC 突触的分子成分以及对声音过敏的性别差异诱发耳蜗损伤，我们将使用功能性（ABR、DPOAE）的强大组合，免疫细胞化学（共焦显微镜）、生物化学、qRT-PCR 和超微结构方法来测试在目标 1 中，我们将确定 IHC 中 GluA3 是否会促进 GluA2 的丰度。在目标 2 中，我们将确定 IHC 突触中的 GluA3 是否可以保护小鼠免受声音诱导的影响。目标 3，根据已发表的数据和我们的初步发现，我们提出假设。在缺乏 GluA3 的情况下，卵巢激素会促进对声音诱发的耳蜗的过敏损害，而雄激素具有保护作用，这些拟议的研究是第一个解决这一问题的研究。 AMPAR 亚基组成的变化如何导致听力损失的性别差异是一个重要问题。