Hearing circadian rhythms.

描述（由申请人提供）：噪音创伤仍然是世界各地听力损失的主要原因。这项探索性资助是基于一项新的发现，该发现显示了噪音引起的听力损失的昼夜变化。听觉系统中的昼夜节律究竟是如何控制的还不清楚。待测试的假设是耳蜗具有内在的昼夜节律钟，其调节听觉系统对噪声创伤的敏感性。 该项目旨在确定这一新发现背后的潜在功能和分子机制。视交叉上核（SCN）是主时钟，其维持和协调节律以调节生理功能，包括代谢、炎症反应、进食、睡眠-觉醒模式和下丘脑垂体肾上腺（HPA轴）。SCN和/或HPA轴可以调节听觉时钟，或者在听觉组织（耳蜗、耳蜗核和下丘）中存在内部时钟。目标1将回答的基本问题，如果昼夜听觉振荡和听觉敏感性创伤是由中央昼夜起搏器SCN控制，或这些振荡发生独立的SCN。目的1的第二部分将确定HPA轴和糖皮质激素在介导听觉昼夜节律噪声引起的损伤中的作用。假设SCN驱动糖皮质激素释放的昼夜节律，如果肾上腺切除术中断输出通路，则完整的SCN将无效。这些实验将说明糖皮质激素如何以及是否参与了听觉时钟节律性的夹带。的最后一部分 目标1将直接测试分离的听觉组织（即，不受SCN或下丘脑-垂体-肾上腺轴的影响）是否具有调节噪声诱导的损伤的内在节律。目的二是研究噪声损伤对PER 2基因敲除小鼠的生理和分子影响，以直接证明PER 2在一天中不同时间调节噪声损伤敏感性的作用。目标2还将确定对噪声创伤的保护和修复是否也有昼夜节律。利用功能和分子技术，我们将描述昼夜节律的影响，噪声损伤和保护机制。这些研究具有临床重要性，因为噪声引起的听力障碍是一个重要的公共卫生问题，并且在人群中呈指数增长。这些新的发现将开辟新的研究途径，并对基础和临床科学具有重要意义。

DESCRIPTION (provided by applicant): Noise trauma continues to be a major cause for hearing loss throughout the world. This exploratory grant is based on the novel finding showing a circadian variation in noise-induced hearing loss. Exactly how this circadian rhythm in the auditory system is controlled is not known. The hypothesis to be tested is that the cochlea has an intrinsic circadian clock that modulates the sensitivity of the auditory system to noise trauma. This project seeks to determine the underlying functional and molecular mechanisms underlying this new finding. The suprachiasmatic nucleus (SCN) is the master clock that synchronizes and coordinates rhythms to regulate physiological functions including metabolism, inflammatory responses, feeding, sleep-wake patterns and the hypothalamic pituitary adrenal (HPA axis). The SCN and/or the HPA axis can be regulating the auditory clock or there is an internal clock in auditory tissues (cochlea, cochlear nucleus and inferior colliculus). Aim 1 will answer the fundamental question if circadian auditory oscillations and auditory sensitivity to trauma is controlled by central circadian pacemaker SCN, or these oscillations occur independently of the SCN. The second part of aim 1 will determine the role of the HPA axis and glucocorticoids in mediating the auditory circadian rhythm noise-induced damage. The assumption is that the SCN drives a circadian rhythm in glucocorticoid release and an intact SCN will not be effective if the output pathway is interrupted by adrenalectomy. These experiments will illustrate how and if glucocorticoids are involved in the entrainment of the auditory clock rhythmicity. The last part of aim 1 will be directly testing if the isolated auditory tissues (i.e. without influence of SCN or te HPA axis) have an intrinsic rhythm that regulates noise-induced damage. Aim 2 will determine the physiological and molecular effects of noise trauma on PER2 knockout mice to directly demonstrate the role of PER2 in regulating sensitivity to noise trauma at different times of the day. Aim 2 will also determine if protection and repair against noise trauma also has a circadian rhythm. Using functional and molecular techniques we will characterize the circadian effect of noise damage and protective mechanisms. These studies are of clinical importance since noise-induced hearing disorders are an important public health issue and are exponentially increasing in the human population. These novel findings will open new avenues of research and have important implications for both basic and clinical science.