Development of a novel high throughput zebrafish model for the study of noise-induced hearing loss

美国数百万人因感觉毛细胞永久性损伤而听力受损 内耳的。毛细胞损伤通常是由于在工作或工作中暴露在过量的声音中造成的 娱乐场所，如工业工作或听吵闹的音乐。有一种严重的未得到满足的需求 更好地理解噪声导致听力损失的潜在机制，并为实验 可用于快速、客观地识别保护性疗法的平台。如果没有 新疗法的发展，对噪声性听力损失将继续产生深远的个人影响 以及经济后果。这项建议的目的是把斑马鱼的横线发展为 使用精确校准的毛细胞损伤系统进行声学过度曝光的宝贵模型。我们的 中心假说是，噪声导致侧线毛细胞损伤的机制类似于 哺乳动物毛细胞的声损伤。该方法提供的初步数据表明 斑马鱼侧线连续噪声损伤范式的发展 高达50%的毛细胞在噪音暴露后的三天内死亡。其基本原理是斑马鱼系统 将使未来的变革性研究能够理解噪声诱导的细胞机制 听力损失，并对新听力进行全面、定量、公正的药物发现研究 保护剂。该项目有两个具体目标：1)确定持续时间之间的精确关联 以及斑马鱼侧线噪声暴露和毛细胞损伤的强度，2)决定了 Caspase激活和氧化应激在噪声诱导毛细胞死亡中的相对作用。这些 建议的研究将使用靶向药理学和活体成像相结合的方式 为斑马鱼侧线定制的新型噪声损伤系统的优化。这个项目是 潜在的创新，因为我们将发展精确调节流体的技术能力 产生会导致损坏的噪音的动力学。预计这一贡献将是 用于噪声性听力损失研究的独特活体实验平台的研制 进一步了解噪音损伤毛细胞中的细胞死亡信号。这些结果将增加我们的 对毛细胞机械性损伤的基本认识和对未来药物开发的积极影响 研究。

Millions of people in the U.S. suffer from hearing loss caused by permanent damage to sensory hair cells of the inner ear. Hair cell damage often results from exposure to excessive sound in occupational or recreational settings such as industrial work or listening to loud music. There is a critical unmet need for greater understanding of the mechanisms underlying noise-induced hearing loss and for an experimental platform that can be used to quickly and objectively identify protective therapies. Without the development of novel therapeutics, noise-induced hearing loss will continue to have profound personal and economic consequences. The objective of this proposal is to develop the zebrafish lateral line as a valuable model for acoustic over-exposure using a precisely calibrated system of hair cell damage. Our central hypothesis is that the mechanism of noise-induced hair cell damage in the lateral line is similar to acoustic trauma in mammalian hair cells. The preliminary data presented in the approach demonstrate development of a continuous noise damage paradigm in the zebrafish lateral line capable of generating up to 50% hair cell death within three days of noise exposure. The rationale is that the zebrafish system will allow for future transformational research to understand cellular mechanisms of noise-induced hearing loss and to conduct thorough, quantitative, unbiased drug discovery research for novel hearing protectants. This project has two specific aims: 1) Determine the precise correlation between the duration and intensity of noise exposure and hair cell damage in the zebrafish lateral line, 2) Determine the relative contributions of caspase activation and oxidative stress to noise-induced hair cell death. These proposed studies will use a combination of targeted pharmacologic and live imaging coupled to optimization of a novel noise damage system customized for the zebrafish lateral line. This project is potentially innovative because we will develop the technical capability of precise regulation of the fluid dynamics delivering the noise that will induce damage. The contribution is expected to be the development of a unique in vivo experimental platform for noise-induced hearing loss research and further understanding cell death signaling in noise-damaged hair cells. These results would increase our fundamental understanding of mechanical hair cell damage and positively impact future drug discovery research.