Circadian regulation of glucocorticoid-dependent inflammation in noise-induced synaptopathy

噪声诱发突触病中糖皮质激素依赖性炎症的昼夜节律调节

• 批准号: 9527912
• 负责人: BARBARA CANLON
• 金额: $ 29.24万
• 依托单位: KAROLINSKA INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9527912
• 关键词: ARNTL gene; Address; Adrenalectomy; Agonist; Auditory; Auditory system; Biological Assay; Brain Stem; Circadian Rhythms; Clock protein; Cochlea; Data; Dendrites; Discipline; Electrophysiology (science); Funding; Gene Expression Regulation; Genes; Genetic; Glucocorticoids; Hair Cells; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Knowledge; Laboratories; Lateral; Maintenance; Measures; Mediating; Messenger RNA; Methods; Molecular; Morphology; Mus; National Institute on Deafness and Other Communication Disorders; Neurons; Neurosciences; Noise; Organ of Corti; Pathway interactions; Pattern; Periodicity; Peripheral; Pharmacologic Substance; Pharmacological Treatment; Physiological; Process; Recovery; Regulation; Reporting; Rest; Sampling; Signal Transduction; Synapses; Techniques; Therapeutic Effect; Time; Tissues; Transcript; Trauma; Treatment Efficacy; Treatment outcome; chemokine; circadian pacemaker; cytokine; drug efficacy; interdisciplinary approach; mouse model; novel; novel therapeutics; prevent; response; ribbon synapse; sound; spiral ganglion; tool; transcriptome sequencing; treatment strategy

Project Summary Through NIDCD funding (R21DC013172) we showed that noise-induced temporary damage to the auditory dendrites is more severe when the exposure occurs at night compared to the day. Preliminary data strongly suggest that circulating glucocorticoids, which peak at nighttime in mice, are responsible for the greater sensitivity to night noise trauma. In absence of circulating glucocorticoids (by adrenalectomy), mice exposed to night noise show complete recovery of their auditory brainstem thresholds, and have their synaptic ribbons protected. RNAseq data show that inflammatory pathways rise at nighttime in the cochlea, and this is abolished in adrenalectomised mice, suggesting that inflammatory response could underlie the greater vulnerability of the auditory synapse. The RNAseq identified 7211 genes in the cochlea that have circadian expression and 65% of these genes show maximal expression at night-time. Since it is not standard practice in the auditory field to collect samples at different time points throughout the day a full understanding of gene regulation during the day and the night in the cochlea is lacking. Our laboratory is currently addressing this challenge with the following aims: Specific Aim 1: To identify glucocorticoid-dependent inflammatory signals that display circadian patterns and are triggered by day or night noise trauma in the cochlea. Hypothesis: GCs modulate inflammatory signals in a circadian manner causing a greater inflammatory response to night noise trauma compared to the day. Specific Aim 2: To determine whether Bmal1 in the cochlea regulates the GC-dependent inflammatory signals in response to day or night noise trauma. Hypothesis: In the cochlea, the core clock protein Bmal1 regulates the circadian cytokine release in response to noise and causing synaptopathy. Specific Aim 3: To develop new pharmacological treatments targeting the circadian machinery to protect from inflammatory-triggered noise-induced synaptopathy. Hypothesis: Inhibition of the clock at nighttime can prevent night noise-induced synaptopathy via the inhibition of inflammatory responses. This project will clarify how circadian and glucocorticoid-dependent inflammatory signals cause cochlear synaptopathy after temporary noise trauma. A battery of functional methods (auditory electrophysiology, noise trauma), quantitative morphological methods (cochleograms, spiral ganglion neuron counts, pre/post synaptic counts) and molecular methods (genetic mouse models, RNA seq) will be used. Ultimately, novel drugs that will modulate circadian rhythms could emerge to prevent and treat from noise-induced synaptopathy. Our results will introduce a new concept to the auditory field, namely, chronopharmacology, where optimal efficacy of drug treatment depends on the time of administration. The novel theoretical concept of this proposal is that the optimal function of the auditory system requires periods of activity followed by rest that is tightly regulated by clock genes. As simple and obvious as this may sound, this concept has neither been previously explored in the context of noise trauma nor treatment strategies.

项目概要 通过 NIDCD 资助 (R21DC013172)，我们发现噪声引起的听觉暂时损伤 与白天相比，夜间暴露时树突的情况更为严重。初步数据有力 表明循环中的糖皮质激素在小鼠夜间达到峰值，是导致更大的 对夜间噪音创伤敏感。在没有循环糖皮质激素的情况下（通过肾上腺切除术），小鼠暴露于 夜间噪音显示他们的听觉脑干阈值完全恢复，并有突触带 受保护。 RNAseq 数据显示耳蜗中的炎症通路在夜间上升，这是 在肾上腺切除小鼠中被废除，表明炎症反应可能是更大的基础 听觉突触的脆弱性。 RNAseq 在耳蜗中鉴定出了 7211 个与昼夜节律相关的基因 表达，其中 65% 的基因在夜间表现出最大表达。由于这不是标准做法 全天不同时间点听觉场采集样本全面了解基因 耳蜗缺乏白天和夜间的调节。我们的实验室目前正在解决这个问题 挑战目标如下： 具体目标 1：识别显示昼夜节律的糖皮质激素依赖性炎症信号 模式，并由耳蜗中的白天或夜间噪音损伤触发。假设：GC 调节 以昼夜节律方式产生炎症信号，对夜间噪音创伤产生更大的炎症反应 与当天相比。 具体目标 2：确定耳蜗中的 Bmal1 是否调节 GC 依赖性炎症 响应白天或夜间噪音创伤的信号。假设：在耳蜗中，核心时钟蛋白 Bmal1 调节昼夜节律细胞因子的释放以响应噪音并引起突触病。 具体目标 3：开发针对昼夜节律机制的新药物治疗方法 防止炎症引发的噪音引起的突触病。假设：时钟的抑制 夜间可以通过抑制炎症反应来预防夜间噪音引起的突触病。 该项目将阐明昼夜节律和糖皮质激素依赖性炎症信号如何导致耳蜗 暂时性噪音创伤后的突触病。一系列功能方法（听觉电生理学、噪声 创伤）、定量形态学方法（耳蜗图、螺旋神经节神经元计数、突触前/后 将使用分子方法（遗传小鼠模型、RNA seq）。最终，新药 调节昼夜节律可能会预防和治疗噪音引起的突触病。我们的 研究结果将为听觉领域引入一个新概念，即时间药理学，其中最佳功效 药物治疗的效果取决于给药时间。该提案的新颖理论概念是 听觉系统的最佳功能需要一段时间的活动和休息，即 受时钟基因严格调控。尽管这听起来简单明了，但这个概念既不 之前曾在噪音创伤或治疗策略的背景下进行过探索。

项目成果

Circadian vulnerability of cisplatin-induced ototoxicity in the cochlea.

• DOI: 10.1096/fj.202001236r
• 发表时间: 2020-10
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Tserga E;Moreno-Paublete R;Sarlus H;Björn E;Guimaraes E;Göritz C;Cederroth CR;Canlon B
• 通讯作者: Canlon B