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

美国有数百万人因感觉毛细胞永久性损伤而导致听力损失。 内耳毛细胞损伤通常是由于职业或工作中暴露于过量的声音而造成的。 娱乐环境，如工业工作或听大声的音乐。有一个关键的未满足的需要， 更深入地了解噪声引起的听力损失的机制， 该平台可用于快速、客观地识别保护性疗法。未经 随着新疗法的发展，噪声性听力损失将继续产生深刻的个人影响。 和经济后果。这项建议的目的是开发斑马鱼侧线作为一种 使用精确校准的毛细胞损伤系统进行声学过度暴露的有价值模型。我们 中心假设是，噪声引起的毛细胞损伤的机制在侧线是类似的， 哺乳动物毛细胞中的声损伤。该方法中提供的初步数据表明， 斑马鱼侧线连续噪声损伤范例的开发能够产生 暴露于噪音三天内毛细胞死亡率高达50%。理论基础是斑马鱼系统 将允许未来的转型研究，以了解噪音诱导的细胞机制， 听力损失和进行彻底的，定量的，公正的药物发现研究，为新的听力 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相关性 和强度的噪声暴露和毛细胞损伤的斑马鱼侧线，2）确定 caspase激活和氧化应激对噪声诱导的毛细胞死亡的相对贡献。这些 拟议的研究将使用靶向药理学和活体成像的组合， 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，因为我们将开发精确调节流体的技术能力， 动力学传递将引起损坏的噪声。预计捐款将是 为噪声性听力损失研究开发独特的体内实验平台， 进一步了解噪声损伤的毛细胞中的细胞死亡信号。这些结果将增加我们的 对机械性毛细胞损伤的基本理解，并对未来的药物发现产生积极影响 research.

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.