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: 8022842
• 负责人: Sharon G Kujawa
• 金额: $ 36.18万
• 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/8022842
• 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; Health; 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; 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; 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）：声学过度暴露是一个日益严重的问题，理解长期后果对公共卫生至关重要。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，最初看起来可逆，不会导致急性或慢性毛细胞损失，在暴露后几个月后跟踪时，会引起螺旋神经节细胞（SGC）的缓慢发作。共聚焦免疫组织化学表明，许多SGC外围末端及其在内毛细胞上的突触在头几天或小时内消失，与声学过度暴露的急性兴奋性毒性一致。我们假设这种急性树突回收会破坏毛细胞之间的正常神经营养蛋白信号传导，支持人工耳蜗上皮的细胞和神经元，并且这种中断引发了SGC中的慢细胞死亡级联。提出的目的是通过表征神经元变性和相关病理生理学的性质和时间过程（AIM 1），以及操纵急性兴奋毒性（AIM 2）或神经营养素表达（AIM 3）（AIM 3）并评估对神经变性的作用来检验这一假设。神经病变的定量（AIM 1A）将在暴露后时间从突触，到外周轴突到细胞体时跟踪变性。在人群反应和单纤维水平（AIM 1B）处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，并将测试噪声会导致自发率低的神经元的优先损失的假设。为了测试急性兴奋毒性是否是神经病的关键上游引起症状，我们利用我们的技术来利用鼠标的耳蜗灌注的技术，这是1）1）用谷氨酸拮抗剂DNQX（AIM 2A）（AIM 2A）阻止噪声诱导的兴奋性兴奋性，2），2）使用瞄准的矩阵（AIMIST AGONIST AGONIST AGONIST AGONIST AMPA（AIM）AIM 2B）（AIM 2）或3）谷氨酸转运蛋白胶（AIM 2C）。为了测试神经营养蛋白在细胞死亡缓慢级联反应中的作用，我们将（通过QRT-PCR，免疫组织化学和NT3-Reporter小鼠）基因表达水平的神经营养蛋白信号通路中关键分子的表达水平水平，以促进/促进促进/促进re neurs的损失； IHC）使用在毛细胞或支持细胞中具有诱导神经营养蛋白过表达的小鼠系（AIM 3B）。了解我们的噪声暴露的小鼠中对缓慢发作的神经退行性变性的性质，病因和可能的预防对人类听力的影响很重要。它表明，原发性神经元损失比以前想象的是获得性感觉性听力损失的更常见和重要方面。这也引起了重要的担忧，可能会出现明显的良性声学过度曝光的长期后果：缓慢发出噪声引起的神经变性的现象可能会以主要方式促进与听力相关的主要抱怨，即在衰老的人群中的问题。公共卫生相关性我们最近在鼠标中的工作表明，噪声曝光，即使是那些似乎导致完全可逆的阈值转移的噪声，实际上使慢性细胞死亡级联反应导致大约一半的神经元素损失，整个大量的神经元素。如果通常适用于哺乳动物的耳朵，因为有充分的理由相信会这样，慢发，噪声引起的，主要的，耳蜗损失的现象可能是一个非常普遍的问题，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现象并使用与人类状况高度相关的耳蜗侮辱（即噪声）来研究其机制。