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：
10670814
负责人：
Maria Eulalia Rubio
金额：
$ 57.91万
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/10670814
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 Surface Swelling Synapses Synaptic Transmission System Testing Western Blotting auditory pathway 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.

项目摘要有关声学环境的所有信息都是由内耳传递到CNS的耳蜗神经。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播人工耳蜗神经（IHC突触）。但是，每种AMPAR亚基对总体的贡献耳蜗中的谷氨酸能受体功能和传入的传播/灵敏度知之甚少。理解这一过程很重要，因为已经涉及AMPAR的谷氨酸兴奋性在噪声，缺血和衰老引起的听力损失的发病机理中。脆弱性的性别差异人类发生听力损失。因此，我们开始研究AMPAR亚基对 IHC突触的传输以及AMPAR亚基的性别特定差异是否存在导致声音引起的人工耳蜗损害和听力损失。基于功能和超微结构初步数据，我们现在假设“ glua3 ampar亚基在性别中起着至关重要的作用双态脆弱性因听力损失。为了机械定义glua3如何贡献结构和 IHC突触的分子成分和性别差异，这是对声音超敏反应的基础引起的人工耳蜗损害，我们将使用功能强大的功能（ABR，DPOAE），免疫细胞化学（共聚焦显微镜），生化，QRT-PCR和超微结构方法测试以下假设。在AIM 1中，我们将确定GLUA3是否促进了IHC的GLUA2的抽象突触。在AIM 2中，我们将确定glua3在IHC突触中是否可以保护小鼠免受声音诱导人工耳蜗损坏。 AIM 3，基于已发布的数据和我们的初步发现，我们提出了假设在没有GLUA3的情况下，卵巢激素促进了声音引起的人耳蜗的超敏反应损坏，而雄激素具有保护作用。这些提出的研究是第一个解决 AMPAR亚基组成的变化如何导致听力丧失的性别差异的重要问题。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of GluA4 in the acoustic and tactile startle responses.

DOI：
10.1016/j.heares.2021.108410
发表时间：
2022-03
期刊：
Hearing research
影响因子：
2.8
作者：
García-Hernández S;Rubio ME
通讯作者：
Rubio ME

The number and distribution of AMPA receptor channels containing fast kinetic GluA3 and GluA4 subunits at auditory nerve synapses depend on the target cells.

DOI：
10.1007/s00429-017-1408-0
发表时间：
2017-11
期刊：
Brain structure & function
影响因子：
3.1
作者：
Rubio ME;Matsui K;Fukazawa Y;Kamasawa N;Harada H;Itakura M;Molnár E;Abe M;Sakimura K;Shigemoto R
通讯作者：
Shigemoto R

Excitation by Axon Terminal GABA Spillover in a Sound Localization Circuit.

声音定位电路中轴突终端 GABA 溢出的激励。

DOI：
10.1523/jneurosci.1132-15.2016
发表时间：
2016
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Weisz,CatherineJC;Rubio,MariaE;Givens,RichardS;Kandler,Karl
通讯作者：
Kandler,Karl

Auditory brainstem development and plasticity.