Circadian Rhythms and Internal Desynchronization

摘要/项目摘要 下丘脑视交叉上核的主起搏点协调昼夜节律 节奏贯穿全身。这些振荡的相位和周期由环境控制。 信号，主要是光。昼夜节律紊乱，如轮班工作和时差反应， 通过我们知之甚少的机制危害健康。我们最近发现了duper， 仓鼠突变，加快了生物钟，并显着加速再夹带 光暗周期转换后的行为节奏。这个突变并不是编码的改变 区域的酪蛋白激酶或任何其他已知的时钟基因，似乎不影响转录- 翻译反馈回路负责细胞自主振荡。我们会找出变种人 等位基因的快速纯合性作图。我们将使用qRT-PCR来检查duper等位基因对 核心时钟和时钟控制基因在心脏，肝脏，肾脏和心脏中表达的昼夜节律相移 肌肉.鉴于对代谢功能至关重要的基因的转录是由多个时钟控制的， 蛋白质或时钟依赖性转录因子，我们将使用RNA-Seq来揭示 转录组范围的相位中断，发生在器官内的转变。我们将使用 免疫细胞化学检查duper对局部SCN功能的影响，并考虑其贡献 起搏器与外围振荡器对再夹带潜伏期的影响。最后，我们将测试 假设昼夜节律的内部去兴奋化是导致扩张性心脏病加重的原因， 在常用的仓鼠模型中，通过重复的相移来观察心肌病。 仓鼠在生物节律的研究中被证明是很有价值的，它们提供了一个独特的工具， 了解心脏病。排卵前LH峰的昼夜节律控制在本研究中得到了很好的理解。 物种，并提供了一个模型，控制下属振荡器的下丘脑起搏器。我们 这项工作将揭示昼夜节律的机制，并使我们能够测试它在疾病中的作用。 鉴于昼夜节律在行为和生理学中的重要性，这项研究将揭示 心脏和肺的病理机制，以及肝脏和肾脏的变化， 导致高血压和纤维化研究结果还将揭示睡眠不足的原因 和代谢紊乱，并可能导致新疗法的开发，以改善人类和 动物健康

Abstract/Project Summary A master pacemaker in the suprachiasmatic nucleus of the hypothalamus coordinates circadian rhythms throughout the body. The phase and period of these oscillations is controlled by environmental signals, principally light. Disruption of circadian organization, such as occurs in shift work and jet lag, compromises health through mechanisms that are poorly understood. We recently discovered duper, a hamster mutation which speeds up the circadian clock and markedly accelerates re-entrainment of behavioral rhythms upon a shift of the light:dark cycle. The duper mutation is not a change in the coding region of casein kinase or any other known clock gene, and seems not to affect the transcriptional- translational feedback loops responsible for cell autonomous oscillations. We will identify the mutant allele by fast homozygosity mapping. We will use qRT-PCR to examine effects of the duper allele upon circadian phase shifts of expression of core clock and clock-controlled genes in heart, liver, kidney, and muscle. Given that transcription of genes critical to metabolic function is controlled by multiple clock proteins or clock-dependent transcription factors, we will use RNA-Seq to reveal the extent of transcriptome-wide phase disruption that occurs within organs during shifts. We will use immunocytochemistry to examine effects of duper on regional SCN function, and factor the contribution of pacemaker vs. peripheral oscillators to the latency of re-entrainment. Finally, we will test the hypothesis that internal desynchronization of circadian rhythms is responsible for aggravation of dilated cardiomyopathy by repeated phase shifts in a commonly used hamster model. Hamsters have proven valuable in studies of biological rhythms, and they offer a unique tool for understanding heart disease. Circadian control of the preovulatory LH surge is well understood in this species and provides a model for control of subordinate oscillators by the hypothalamic pacemaker. Our work will shed light on the mechanisms of circadian desynchrony and allow us to test its role in disease. Given the importance of circadian organization in behavior and physiology, this research will reveal mechanisms that underlie pathologies of heart and lung, as well as changes in liver and kidney that contribute to hypertension and fibrosis. The results will also shed light on causes of sleep deficiencies and metabolic disorders, and are likely to lead to development of new therapies to improve human and animal health.