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

开发用于研究噪声引起的听力损失的新型高通量斑马鱼模型

• 批准号: 9313454
• 负责人: ALLISON B COFFIN
• 金额: $ 27.05万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313454
• 关键词: Acoustic Trauma; Acoustics; American; Antioxidants; Attenuated; Biological Models; Caspase; Caspase Inhibitor; Cell Death; Cell Death Signaling Process; Cells; Cellular biology; Chemicals; Cochlea; Coupled; Custom; Data; Development; Economics; Event; Exposure to; Fishes; Future; Genetic; Hair; Hair Cells; Head; Hearing; Hour; Human; Image; Imaging Techniques; In Vitro; Industrialization; Labyrinth; Liquid substance; Loudness; Mammals; Mechanics; Mediating; Methods; Modeling; Morphology; Music; Noise; Noise-Induced Hearing Loss; Occupational; Organ; Oxidative Stress; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Physiology; Prevention; Reactive Oxygen Species; Regulation; Research; Sensory; Sensory Hair; Signal Transduction; Study models; Synapses; System; Testing; Therapeutic Intervention; Time; Trauma; Work; Zebrafish; aminoglycoside-induced ototoxicity; cell injury; cellular imaging; collaborative environment; combat; deafness; drug development; drug discovery; hearing impairment; in vivo; in vivo Model; innovation; insight; killings; lateral line; neuromast; novel; novel therapeutics; ototoxicity; prevent; sound; systems research; targeted treatment; therapeutic target

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.

美国数百万人因感觉毛细胞永久性损伤而遭受听力损失 内耳的。毛细胞损伤通常是由于职业或工作中暴露于过多的声音造成的 娱乐场所，例如工业工作或听大声的音乐。有一个未满足的关键需求 更好地了解噪声引起的听力损失的机制并进行实验 可用于快速、客观地识别保护性疗法的平台。如果没有 随着新疗法的发展，噪音引起的听力损失将继续对个人产生深远的影响 和经济后果。该提案的目标是将斑马鱼侧线发展为 使用精确校准的毛细胞损伤系统来进行声学过度暴露的有价值的模型。我们的 中心假设是噪声引起的侧线毛细胞损伤的机制类似于 哺乳动物毛细胞的声损伤。该方法中提供的初步数据表明 在斑马鱼侧线中开发连续噪声损伤范例，能够产生 噪声暴露三天内毛细胞死亡高达 50%。其基本原理是斑马鱼系统 将允许未来的转化研究了解噪音引起的细胞机制 听力损失并进行彻底、定量、公正的新听力药物发现研究 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相关性 噪声暴露和斑马鱼侧线毛细胞损伤的强度，2) 确定 半胱天冬酶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 拟议的研究将结合靶向药理学和实时成像 优化针对斑马鱼侧线定制的新型噪声损伤系统。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 动力学产生的噪音会导致损坏。该贡献预计为 开发独特的体内实验平台，用于噪声引起的听力损失研究和 进一步了解噪声损伤毛细胞中的细胞死亡信号传导。这些结果将增加我们的 对机械毛细胞损伤的基本了解并对未来的药物发现产生积极影响 研究。