Drosophila model for noise-induced hearing loss

描述(由申请人提供)：我们对噪音导致的听力损失的理解是相当初级的，尽管这个问题对人类的职业和娱乐健康很重要。这种损害是永久性的，因为哺乳动物一旦死亡就不能再生它们的听觉毛细胞。对噪声导致听力损失的根本原因的研究主要集中在细胞的机械性损伤上，而分子研究则集中在氧化损伤和细胞骨架破坏上。哺乳动物的研究面临着难以接触到颞骨内的内耳以及昂贵的动物护理费用的挑战。在这项建议中，我们试图利用遗传模式生物--果蝇--来系统地表征急性或慢性过度暴露于声音所引起的基因表达变化。我们的初步结果表明，急性暴露后对听觉功能有很强的即刻影响。我们建议首先研究这些形式的噪声创伤的直接和长期的形态和生理后果。其次，我们将使用微阵列分析来确定全基因组对声应力的响应。这些研究将提供可能的途径，通过这些途径增加对噪音损害的抵抗力，作为预防措施，或减少噪音损害的有害影响，作为一种治疗措施。他们还将告知个体对噪音损害易感性的遗传差异。 与公共健康相关：在当今的工业和技术世界，过度暴露在噪音中是一个严重的问题，特别是随着人类人口年龄结构的增加。拟议的项目使用遗传模式生物果蝇来研究急性或慢性过度暴露于声音时对听觉器官的功能和结构影响，并了解这种治疗引起的基因表达变化。我们的研究结果将有助于确定人类噪声性听力损失和年龄相关性听力损失的假定预防和治疗靶点。

DESCRIPTION (provided by applicant): Our understanding of Noise-Induced Hearing Loss is rather rudimentary, despite the importance of this problem to human occupational and recreational health. The damage is permanent because mammals cannot regenerate their auditory hair cells once they die. Studies of the underlying causes of noise-induced hearing loss have focused on mechanical damage to cells, and molecular studies centered around oxidative damage and cytoskeletal disruptions. Mammalian studies are challenged by difficult access to the inner ear inside the temporal bone, and expensive animal care costs. In this proposal we seek to capitalize on the genetic model organism, Drosophila, to systematically characterize gene expression changes induced by acute or chronic over-exposure to sound. Our preliminary results show that there are strong immediate effects on auditory function after acute exposure. We propose first to study the immediate and longer-term morphological and physiological consequences of these forms of noise trauma. Second, we will identify genome-wide responses to acoustic stress using microarray analysis. These studies will provide insight into possible pathways through which to increase resistance to noise damage as a preventative measure, or to reduce the deleterious effects of noise damage after the fact as a therapeutic measure. They will also inform the individual genetic differences in susceptibility to noise damage. PUBLIC HEALTH RELEVANCE: Over-exposure to noise is a serious problem in today's industrial and technological world, especially with increasing age structure in human populations. The proposed project uses the genetic model organism Drosophila to investigate functional and structural consequences to the auditory organ upon acute or chronic over-exposure to sound, and to understand gene expression changes evoked by this treatment. The results of our studies will facilitate identification of putative preventative and therapeutic targets for human noise-induced hearing loss and age-related hearing loss.