Mechanisms of hypersensitivity to sound-induced cochlear damage

对声音引起的耳蜗损伤过敏的机制

• 批准号: 10200747
• 负责人: Maria Eulalia Rubio
• 金额: $ 58.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/10200747
• 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

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 所有关于声环境的信息都是由内耳的传入纤维传递到中枢神经系统的。 耳蜗神经快速门控AMPA谷氨酸受体（AMPAR; GluA 2、GluA 3和GluA 4亚基） 在内毛细胞（IHC）和传入纤维之间的成熟突触处介导突触传递 耳蜗神经（IHC突触）。然而，每种类型的AMPAR亚基对整体的贡献是不同的。 耳蜗中的神经元能受体功能和传入传递/敏感性知之甚少。 了解这一过程是重要的，因为谷氨酸兴奋毒性通过AMPAR已牵连 在噪声、缺血和衰老引起的听力损失的发病机制中。在易受艾滋病毒/艾滋病感染方面的性别差异 听力损失发生在人类身上。因此，我们开始研究AMPAR亚基对 在免疫组化突触的传输，以及是否有性别特异性差异的AMPAR亚基， 导致声音引起的耳蜗损伤和听力损失。基于功能和超微结构 根据初步数据，我们现在假设“GluA 3 AMPAR亚基在性发育中起关键作用， 二态性听力损失”。为了从机制上定义GluA 3如何促进结构和功能， IHC突触的分子成分和对声音敏感性的性别差异， 诱发耳蜗损伤，我们将使用功能（ABR，DPOAE）， 免疫细胞化学（共聚焦显微镜），生物化学，qRT-PCR和超微结构方法来测试 根据假设。在目标1中，我们将确定GluA 3是否促进IHC中GluA 2的丰度 突触在目标2中，我们将确定IHC突触上的GluA 3是否保护小鼠免受声音诱导的损伤。 耳蜗损伤目的3，基于已发表的数据和我们的初步研究结果，我们提出了假设 在缺乏GluA 3的情况下，卵巢激素促进了对声音诱导的耳蜗的超敏反应。 损伤，而雄激素具有保护作用。这些拟议的研究是第一个解决 AMPAR亚基组成的变化如何导致听力损失的性别差异。