Molecular Mechanisms in Noise-Induced Hearing Loss

摘要 噪声性听力损失（NIHL）在工业化国家越来越普遍， 工作场所噪音暴露和休闲活动。与其功能缺陷相对应， 外毛细胞（OHC）和突触带是主要的内耳病理。虽然各种 已经报告了与OHC死亡相关的生化和病理事件，目前没有 预防或治疗NIHL的既定临床疗法，主要是由于缺乏一种 全面了解精确的分子机制和信号通路介导的OHC 损伤和损失突触带响应噪声暴露。这项研究的长期目标是 了解导致NIHL的分子机制，并阐明新的和合理的药理学 或分子/遗传治疗干预以改善或预防NIHL。我们此前曾报道， 创伤性噪声瞬时消耗细胞能量储备并增加能量传感器P的水平， OHC中的AMPKα。我们令人兴奋的新的初步结果显示， 线粒体钠钙交换器（NCLX）蛋白的数量减少， 噪声暴露后的OHC。这些变化的幅度与噪声强度呈正相关。 此外，这种变化发生继发于噪声引起的能量消耗和钙的流入。基于 根据这些数据，提出了噪声引起的MCU增加将钙移动到 而NCLX的抑制减少了钙从线粒体中的挤出， 共同造成线粒体钙超载。我们将使用一个全面的 采用成年小鼠体内研究和一种新的体外能量模型的实验方法 在内耳细胞系模型中进行的用于测试NIHL分子机制的特定方面的细胞耗竭。我们 还将使用基因敲除小鼠、siRNA、基因治疗和药物化合物来阻断选择的 促进线粒体钙超载的途径，试图实现协同保护， NIHL。本课题的研究结果将为NIHL的机理提供新的认识，并对NIHL的设计提供指导 预防NIHL的新型干预措施，有利于个人的生活质量， 医疗费用。此外，本提案中产生的数据将对我们的 了解广泛的内耳疾病，因为相似之处已经注意到， 与噪声、药物和年龄相关性听力损失相关的分子事件。

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.