Molecular Mechanisms in Noise-Induced Hearing Loss

噪声性听力损失的分子机制

• 批准号: 9204820
• 负责人: Su-Hua Sha
• 金额: $ 31.77万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204820
• 关键词: Address; Adult; Affect; Biochemical; CBA/J Mouse; Calcium; Cell Death; Cell Line; Cells; Clinical; Data; Deoxyglucose; Developed Countries; Dose; Event; Goals; Hair Cells; Health Care Costs; Individual; Knockout Mice; Labyrinth; Leisure Activities; Mediating; Mental Depression; Messenger RNA; Mitochondria; Modeling; Molecular; Molecular Genetics; Mus; Noise; Noise-Induced Hearing Loss; Oligomycins; Organ of Corti; Outcome; Outer Hair Cells; Pathologic; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Preparation; Presbycusis; Prevention therapy; Preventive Intervention; Proteins; Quality of life; Quantitative Reverse Transcriptase PCR; Reporting; Research; Secondary to; Sensory Hair; Signal Pathway; Signal Transduction; Small Interfering RNA; Sodium-Calcium Exchanger; Surface; Testing; Therapeutic Intervention; Western Blotting; Work; Workplace; adeno-associated viral vector; base; calcium uniporter; cell injury; design; disability; experimental study; gene therapy; in vitro Model; in vivo; inhibitor/antagonist; inner ear diseases; innovation; insight; mutant; novel; prevent; response; ribbon synapse; sensor; stem; success; uptake

Abstract Noise-induced hearing loss (NIHL) is becoming increasingly common in industrialized countries, stemming from both workplace noise exposure and leisure activities. Corresponding with its functional deficit, loss of outer hair cells (OHCs) and synaptic ribbons are the primary inner ear pathology. Although a variety of biochemical and pathological events associated with OHC death have been reported, there is currently no established clinical therapy for the prevention or treatment of NIHL, owing largely to the lack of a comprehensive understanding of the precise molecular mechanisms and signaling pathways mediating OHC injury and loss of synaptic ribbons in response to noise exposure. The long-term goal of this research is to understand the molecular mechanisms that result in NIHL and to elucidate novel and rational pharmacological or molecular/genetic therapeutic interventions to ameliorate or prevent NIHL. We have previously reported that traumatic noise transiently depletes cellular energy reserves and increases levels of the energy sensor p- AMPKα in OHCs. Our exciting new preliminary results show an increased amount of mitochondrial calcium uniporter (MCU) and a decreased amount of the mitochondrial sodium calcium exchanger (NCLX) proteins in OHCs after noise exposure. The magnitude of these changes is positively correlated with noise intensity. Furthermore, such changes occur secondarily to noise-induced energy depletion and influx of calcium. Based on these data, the hypothesis is presented that the noise-induced increase of MCU moves calcium into mitochondria while the depression of NCLX reduces the extrusion of calcium out of mitochondria, actions that together create mitochondrial calcium overload. We will address this hypothesis using a comprehensive experimental approach employing both in-vivo studies with adult mice and a novel in-vitro model of energy depletion in an inner ear cell line model for testing specific aspects of the molecular mechanisms of NIHL. We also will use knockout mice, siRNA, gene therapy, and pharmacological compounds to block selected pathways that promote mitochondrial calcium overload in an attempt to achieve synergistic protection against NIHL. The results of this project will lead to new insights into mechanisms of NIHL and may direct the design of novel interventions for the prevention of NIHL benefiting the quality of life of individuals and reducing healthcare costs. In addition, the data generated in this proposal will make a significant contribution to our understanding of a broad range of inner ear disorders, since similarities have already been noted in the molecular events associated with noise-induced, drug-induced, and age-related hearing loss.

抽象的 噪声引起的听力损失（NIHL）在工业化国家越来越普遍， 从工作场所的噪音曝光和休闲活动中。与其功能不足相对应 外毛细胞（OHC）和突触丝带是主要的内耳病理学。虽然各种各样 据报道与OHC死亡相关的生化和病理事件，目前没有 建立的用于预防或治疗NIHL的临床疗法主要是由于缺乏 对介导OHC的精确分子机制和信号通路的全面了解 响应噪声暴露的伤害和突触丝带的丧失。这项研究的长期目标是 了解导致NIHL的分子机制，并阐明新颖和合理的药物 或分子/基因治疗干预措施以改善或预防NIHL。我们以前已经报道了 创伤性噪声会瞬时耗尽细胞能量储量，并增加能量传感器p-的水平 OHC中的AMPKα。我们令人兴奋的新初步结果表明，线粒体钙的数量增加 单位器（MCU）和降低的线粒体钠钙交换剂（NCLX）蛋白 噪声暴露后的OHC。这些变化的大小与噪声强度正相关。 此外，这种变化发生在噪声诱导的能量耗竭和钙的影响下。基于 在这些数据上，提出了噪声引起的MCU的增加的假设将钙移至 线粒体虽然NCLX的抑郁会降低钙从线粒体中的扩展，这是 共同创建线粒体钙过载。我们将使用全面解决这一假设 实验方法采用成年小鼠和新型能量模型的体内研究采用实验方法 内耳耳细胞系模型中的耗竭，用于测试NIHL分子机制的特定方面。我们 还将使用基因敲除小鼠，siRNA，基因疗法和药物化合物来阻断选定的 促进线粒体钙超负荷的途径，以实现协同保护 NIHL。该项目的结果将导致对NIHL机制的新见解，并可能指导设计 预防NIHL的新干预措施使个人的生活质量受益并减少 医疗保健费用。此外，本提案中产生的数据将为我们的 了解广泛的内耳障碍，因为已经在 与噪声引起的，药物诱导的和年龄相关的听力损失相关的分子事件。