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: 7769547
• 负责人: Sharon G Kujawa
• 金额: $ 37.37万
• 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/7769547
• 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; Chronic; Clinical Research; Cochlea; Cochlear Nerve; Complement; Coupled; DNQX; Data; Deterioration; Development; 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; Noise; Noise-Induced Hearing Loss; Performance; Perfusion; Peripheral; Pharmacology; Population; Presbycusis; Presynaptic Terminals; Prevention; Process; Public Health; 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; Time; Tissues; Transgenic Mice; Work; age related; excitotoxicity; ganglion cell; insight; mouse model; mutant; nerve supply; neuron loss; neuronal cell body; neurotensin mimic 2; neurotransmission; neurotrophic factor; novel strategies; otoacoustic emission; overexpression; prevent; public health relevance; 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)：声学过量暴露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小鼠模型中的工作表明，中等暴露，最初似乎是可逆的，不会导致急性或慢性毛细胞损失，但在暴露后几个月的跟踪调查中，会导致螺旋神经节细胞(SGCs)缓慢发生损失。共聚焦免疫组织化学显示，许多SGC外周终末及其在内毛细胞上的突触在最初的几天或几个小时内消失，这与声过度暴露的急性兴奋毒性效应一致。我们推测，这种急性树突回缩扰乱了毛细胞、支持细胞和耳蜗上皮神经元之间的正常神经营养因子信号，并且这种干扰启动了SGCs中缓慢的细胞死亡级联反应。拟议的AIMS通过描述神经元退变及相关病理生理学的性质和时间进程(AIM 1)，以及通过操纵急性兴奋性毒性(AIM 2)或神经营养素表达(AIM 3)并评估其对耳蜗神经退行性变的影响来验证这一假说。神经病变的量化(目标1a)，将跟踪暴露后时间内从突触到外周轴突再到细胞体的退化情况。在群体反应和单纤维水平(目标1b)与病理生理学的相关性将验证我们是否已经确定了重要的功能结构变化，并将检验噪声导致低自发频率神经元优先丢失的假设。为了测试急性兴奋毒性是否是神经病变的关键上游激发子，我们利用我们的技术在小鼠耳蜗处进行灌流，以1)用谷氨酸拮抗剂DNQX(目标2a)阻断噪声诱导的兴奋毒性，2)用谷氨酸激动剂AMPA(目标2b)模拟它，或3)通过靶向缺失谷氨酸转运体GLAST(目标2c)增强它。为了测试神经营养因子在细胞死亡的慢级联反应中的作用，我们将(通过qRT-PCR、免疫组织化学和NT3报告鼠)检测神经营养因子信号通路中关键分子的基因表达水平随暴露后时间的变化(目标3a)，并尝试一项救援实验(减少/防止神经元丢失；促进完整IHC的再神经支配)，使用毛细胞或支持细胞中可诱导的神经营养因子过表达的小鼠系(目标3b)。了解噪声暴露小鼠迟发性神经变性的性质、病因和可能的预防措施对人类听力具有重要的影响。这表明，原发神经元丢失是获得性感音神经性听力损失的一个比先前认为的更常见和更重要的方面。这也引起了人们对表面上良性的声音过度暴露可能产生的长期后果的重要关注：缓慢起效的噪声诱导的神经退化现象可能在很大程度上导致老年人与听力相关的主要症状，即在嘈杂环境中理解语言的问题。公共健康相关性我们最近在小鼠身上的研究表明，噪声暴露，即使是那些似乎导致完全可逆的阈值移动的噪声暴露，实际上也会启动一个缓慢的细胞死亡级联反应，导致耳蜗大片区域大约一半的神经元件最终丧失。如果普遍适用于哺乳动物的耳朵，那么有充分的理由相信它将是如此，慢发、噪音诱导的原发耳蜗神经丢失现象可能是一个非常常见的问题，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索其机制，使用与人类状况高度相关的耳蜗性侮辱(即噪声)。