Hearing circadian rhythms.

描述(申请人提供)：噪音创伤仍然是全世界听力损失的主要原因。这项探索性拨款是基于一项新的发现，该发现表明噪音导致的听力损失存在昼夜变化。听觉系统中的这种昼夜节律到底是如何控制的，目前尚不清楚。要检验的假设是，耳蜗有一个内在的生物钟，调节听觉系统对噪音创伤的敏感性。 该项目试图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)是同步和协调节律以调节生理功能的主时钟，这些生理功能包括新陈代谢、炎症反应、摄食、睡眠-觉醒模式和下丘脑-垂体-肾上腺(HPA轴)。SCN和/或HPA轴可以调节听钟，或者在听觉组织(耳蜗核、耳蜗核和下丘)中存在内钟。目的1将回答一个基本问题，即昼夜听觉振荡和对创伤的听觉敏感性是由中央昼夜节律起搏器SCN控制的，还是这些振荡独立于SCN发生。目标1的第二部分将确定HPA轴和糖皮质激素在调节噪声引起的听觉昼夜节律损伤中的作用。假设SCN驱动糖皮质激素释放的昼夜节律，如果输出通路被肾上腺切除中断，完整的SCN将不起作用。这些实验将阐明糖皮质激素如何以及是否参与听觉时钟节律性的调节。的最后一部分 目标1将直接测试分离的听觉组织(即在不受SCN或TE HPA轴影响的情况下)是否具有调节噪声诱导的损伤的内在节律。目的2测定噪声创伤对PER2基因敲除小鼠的生理和分子效应，以直接证实PER2在一天中不同时间段对噪声创伤敏感性的调节作用。目标2还将确定对噪音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，我们将描述噪声损伤的昼夜节律效应和保护机制。这些研究具有重要的临床意义，因为噪声引起的听力障碍是一个重要的公共卫生问题，而且在人类人口中呈指数级增长。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.