Basic and Clinical Studies of Noise-Induced and Age-Related Hearing Loss

噪声引起的和与年龄相关的听力损失的基础和临床研究

• 批准号: 7464042
• 负责人: Sharon G Kujawa
• 金额: $ 37.75万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-05 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464042
• 关键词: 3-Dimensional; Acoustic Nerve; Acoustic Trauma; Acoustics; Acute; Address; Age; Aging; Animals; Area; Auditory; Axon; Benign; Biological Assay; Biology; Brain-Derived Neurotrophic Factor; Cell Death; Chromosome Pairing; Chronic; Clinical Research; Cochlea; Cochlear Nerve; Complement; Condition; Count; Coupled; DNQX; Data; Deterioration; Development; Disruption; Down-Regulation; Drug Delivery Systems; Ear; Electrophysiology (science); Elements; Environment; Epithelium; Etiology; Evaluation; Event; Excitatory Amino Acid Antagonists; Exposure to; Fiber; Functional disorder; GLAST Protein; Gene Expression; Genetic; Glutamate Agonist; Glutamate Transporter; Glutamates; Hair Cells; Hearing; Hour; Human; Immunohistochemistry; Infusion procedures; Injury; Inner Hair Cells; Interruption; Labyrinth; Link; Literature; Measurement; Mediating; Molecular Biology; Motion; Mus; NTF3 gene; Natural regeneration; Nature; Nerve Degeneration; Neuregulins; Neurons; Neuropathy; Neurotrophic Tyrosine Kinase Receptor Type 2; Neurotrophin 3; Noise; Noise-Induced Hearing Loss; Performance; Perfusion; Peripheral; Pharmacology; Population; Presbycusis; Presynaptic Terminals; Prevention; Process; Protein Overexpression; Public Health; Rate; Recovery; Reporter; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Secondary to; Sensorineural Hearing Loss; Signal Pathway; Signal Transduction; Site; Speech; Stereocilium; Supporting Cell; Swelling; Synapses; System; Techniques; Testing; Therapeutic Intervention; Thinking; Time; Tissues; Transgenic Mice; Week; Work; age related; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; day; excitotoxicity; ganglion cell; insight; mouse model; mutant; nerve supply; neuron loss; neuronal cell body; neurotensin mimic 2; neurotransmission; neurotrophic factor; novel strategies; otoacoustic emission; prevent; receptor; reconstruction; reinnervation; relating to nervous system; research study; response; spiral ganglion; uptake

DESCRIPTION (provided by applicant): Acoustic overexposure is a growing problem, and understanding the long-term consequences is critical to public health. Our recent work in a mouse model of noise and aging shows that moderate exposures, which initially appear reversible and cause no acute or chronic hair cell loss, elicit a slow-onset loss of spiral ganglion cells (SGCs) when followed for months post-exposure. Confocal immunohistochemistry suggests that many SGC peripheral terminals, and their synapses on inner hair cells, disappear within the first days or hours, consistent with acute excitotoxic effects of acoustic overexposure. We hypothesize that this acute dendritic retraction disrupts normal neurotrophin signaling among hair cells, supporting cells and neurons in the cochlear epithelium, and that this interruption initiates the slow cell-death cascade in SGCs. The proposed Aims test this hypothesis by characterizing the nature and time course of neuronal degeneration and associated pathophysiology (Aim 1), and by manipulating acute excitotoxicity (Aim 2) or neurotrophin expression (Aim 3) and assessing the effects on cochlear neurodegeneration. Quantification of neuropathy (Aim 1a), will track degeneration over post-exposure time as it progresses from synapse, to peripheral axon, to cell body. Correlations with pathophysiology at population-response and single-fiber levels (Aim 1b) will verify if we have identified the functionally important structural changes, and will test the hypothesis that noise causes a preferential loss of neurons with low spontaneous rates. To test if acute excitotoxicity is the key upstream elicitor of the neuropathy, we exploit our techniques for cochlear perfusion in mouse to either 1) block noise-induced excitotoxicity with the glutamate antagonist DNQX (Aim 2a), 2) mimic it with the glutamate agonist AMPA (Aim 2b) or 3) enhance it using mice with targeted deletion of the glutamate transporter GLAST (Aim 2c). To test the role of neurotrophins in the slow cascade of cell death, we will assay (via qRT-PCR, immunohistochemistry and a NT3-reporter mouse) gene expression levels of key molecules in the neurotrophin signaling pathway as a function of post-exposure time (Aim 3a), and attempt a rescue experiment (reduce/prevent loss of neurons; promote re-innervation of intact IHCs) using mouse lines with inducible neurotrophin overexpression in either hair cells or supporting cells (Aim 3b). Understanding the nature, etiology and possible prevention of slow-onset neurodegeneration in our noise- exposed mice has important ramifications for human hearing. It suggests that primary neuronal loss is a more common and important aspect of acquired sensorineural hearing loss than previously thought. It also raises important concerns re possible long-term consequences of apparently benign acoustic overexposures: the phenomenon of slow-onset noise-induced neurodegeneration may contribute in a major way to the main hearing-related complaint in aging humans, i.e. problems understanding speech in a noisy environment. PUBLIC HEALTH RELEVANCE Our recent work in mouse shows that noise-exposures, even those that appear to result in fully reversible threshold shifts, actually set in motion a slow cell death cascade leading to the ultimate loss of roughly half of the neural elements throughout large regions of the cochlea. If generally applicable to the mammalian ear, as there is every reason to believe it will be, the phenomenon of slow-onset, noise-induced, primary, cochlear-nerve loss is potentially a very common problem with significant public health implications. Our proposed experiments provide a powerful platform to study the phenomenon and to probe its mechanisms, using a cochlear insult (i.e. noise) that is highly relevant to the human condition.

描述（由申请人提供）：声学过度是一个日益严重的问题，了解其长期后果对公众健康至关重要。我们最近在噪声和衰老的小鼠模型中的工作表明，中等暴露，最初似乎是可逆的，不会引起急性或慢性毛细胞损失，在暴露后几个月内引起螺旋神经节细胞（SGCs）的缓慢损失。共聚焦免疫组化表明，许多SGC外周末梢，和他们的内毛细胞上的突触，消失在第一天或数小时内，符合急性兴奋性毒性作用的声音过度。我们推测，这种急性树突状回缩破坏了耳蜗上皮中毛细胞、支持细胞和神经元之间的正常神经营养因子信号传导，并且这种中断启动了SGCs中的缓慢细胞死亡级联反应。提出的目的通过表征神经元变性和相关病理生理学（目的1）的性质和时程，以及通过操纵急性兴奋性毒性（目的2）或神经营养因子表达（目的3）并评估对耳蜗神经变性的影响来检验这一假设。神经病变的定量（目标1a）将在暴露后时间内跟踪变性，因为它从突触发展到外周轴突，再到细胞体。在群体反应和单纤维水平（目的1b）的病理生理学的相关性将验证我们是否已经确定了功能上重要的结构变化，并将测试噪声导致低自发率神经元的优先损失的假设。为了测试急性兴奋性毒性是否是神经病的关键上游诱发物，我们利用我们的小鼠耳蜗灌注技术来1）用谷氨酸拮抗剂DNQX（Aim 2a）阻断噪声诱导的兴奋性毒性，2）用谷氨酸激动剂AMPA（Aim 2b）模拟它，或3）使用具有谷氨酸转运蛋白GLAST靶向缺失的小鼠（Aim 2c）增强它。为了测试神经营养因子在细胞死亡的缓慢级联中的作用，我们将测定（通过qRT-PCR、免疫组织化学和NT 3-报告小鼠）神经营养因子信号传导途径中关键分子的基因表达水平作为暴露后时间的函数（Aim 3a），并尝试挽救实验（减少/防止神经元的损失;促进完整IHC的神经再支配），使用在毛细胞或支持细胞中具有可诱导神经营养因子过表达的小鼠系（目的3b）。了解我们的噪声暴露小鼠中的慢性神经变性的性质、病因和可能的预防对人类听力具有重要的影响。这表明，原发性神经元损失是获得性感音神经性听力损失比以前认为的更常见和重要的方面。这也引起了人们对明显良性的声音过度暴露可能产生的长期后果的重要关注：缓慢发作的噪声诱导的神经变性现象可能主要导致老年人的主要听力相关投诉，即在嘈杂环境中理解语音的问题。公共卫生相关性我们最近在老鼠身上的研究表明，即使是那些看起来会导致完全可逆的阈值偏移的噪声暴露，实际上也会启动一个缓慢的细胞死亡级联反应，导致耳蜗大面积区域中大约一半的神经元件最终丢失。如果普遍适用于哺乳动物的耳朵，因为有充分的理由相信它会，缓慢发病的现象，噪音诱导的，主要的，耳蜗神经损失是一个潜在的非常常见的问题，具有重大的公共卫生影响。我们提出的实验提供了一个强大的平台来研究这一现象，并探讨其机制，使用耳蜗侮辱（即噪音），这是高度相关的人类条件。