Molecular Mechanisms in Noise-Induced Hearing Loss

摘要 噪声性听力损失(NIHL)在工业化国家变得越来越普遍， 工作场所噪音暴露和休闲活动。与其功能缺陷相对应，丧失 外毛细胞和突触带是内耳的主要病理改变。虽然有各种各样的 与OHC死亡有关的生化和病理事件已有报道，目前没有 已建立的预防或治疗NIHL的临床疗法，主要是由于缺乏 全面了解OHC的确切分子机制和信号通路 噪声暴露引起的突触带损伤和丢失。这项研究的长期目标是 了解NIHL的分子机制，阐明新的合理的药理作用 或分子/基因治疗干预，以改善或预防NIHL。我们之前已经报道过， 创伤噪声会瞬间耗尽细胞的能量储备，并增加能量传感器的水平。 外周血细胞的AMPKα。我们令人兴奋的新的初步结果显示线粒体钙的数量增加 单转运体(MCU)和线粒体钠钙交换器(NCLX)蛋白的数量减少 噪声暴露后出现心跳。这些变化的大小与噪声强度呈正相关。 此外，这种变化继而发生在噪音引起的能量耗竭和钙离子内流。基座 根据这些数据，提出了一个假设，即噪音导致的MCU增加将钙转移到 虽然NCLX的抑制减少了钙从线粒体中排出，但这种作用 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 用于测试NIHL分子机制的特定方面的内耳细胞系模型中的耗竭。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 促进线粒体钙超载的途径，试图实现协同保护 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 预防新生儿急性淋巴细胞性白血病的新干预措施，有益于个人的生活质量并减少 医疗保健成本。此外，这份提案中产生的数据将对我们的 对广泛的内耳疾病的了解，因为在 与噪声诱导、药物诱导和年龄相关的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.