Hearing circadian rhythms.

聆听昼夜节律。

基本信息

批准号：
8652446
负责人：
BARBARA CANLON
金额：
$ 13.67万
依托单位：
KAROLINSKA INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8652446
关键词：
Acoustic Trauma Adrenal Glands Adrenalectomy Affect Animals Auditory Auditory system Basic Science Biological Clocks Chimeric Proteins Circadian Rhythms Clinical Clinical Sciences Clock protein Cochlea Cochlear nucleus Collection Corticosterone Effectiveness Environment Feedback Genes Glucocorticoids Grant Hearing Hearing problem Hormonal Human Hypothalamic structure Inferior Colliculus Inflammatory Response Knockout Mice Light Location Luciferases Mediating Messenger RNA Metabolism Methods Molecular Mus Noise Noise-Induced Hearing Loss Output Pathway interactions Pattern Periodicity Peripheral Physiological Pituitary Gland Play Population Predisposition Public Health Reaction Reporter Research Role Signal Transduction Sleep Steroids Stress Structure System Techniques Testing Time Tissues Transgenic Mice Trauma Travel Variant base circadian pacemaker clinically relevant feeding hearing impairment hypothalamic-pituitary-adrenal axis knockout animal novel public health relevance repaired research study response suprachiasmatic nucleus

项目摘要

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.

描述（由申请人提供）：噪声创伤仍然是全世界听力损失的主要原因。这项探索性资助基于一项新发现，该发现显示噪声引起的听力损失存在昼夜节律变化。听觉系统中的昼夜节律究竟是如何控制的尚不清楚。要测试的假设是耳蜗有一个内在的生物钟，可以调节听觉系统对噪音创伤的敏感性。该项目旨在确定这一新发现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，包括新陈代谢、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 将回答昼夜节律听觉振荡和对创伤的听觉敏感性是否由中央昼夜节律起搏器 SCN 控制的基本问题，或者这些振荡独立于 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，并且如果输出途径被肾上腺切除术中断，完整的 SCN 将不起作用。这些实验将说明糖皮质激素如何以及是否参与听觉时钟节律的控制。最后一部分目标 1 将直接测试孤立的听觉组织（即不受 SCN 或 te HPA 轴的影响）是否具有调节噪声引起的损伤的内在节律。目标2将确定噪音创伤对PER2基因敲除小鼠的生理和分子影响，以直接证明PER2在一天中不同时间调节对噪音创伤的敏感性的作用。目标 2 还将确定针对噪声创伤的保护和修复是否也具有昼夜节律。使用功能和分子技术，我们将描述噪声损害和保护机制的昼夜节律效应。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级增长。这些新发现将开辟新的研究途径，并对基础科学和临床科学产生重要影响。