Circadian Rhythms and Internal Desynchronization

摘要/项目摘要 下丘脑视交叉上核内的主起搏器协调昼夜节律 全身的节奏。这些振荡的相位和周期是由环境控制的。 信号，主要是光。打乱昼夜节律，如倒班工作和时差， 通过鲜为人知的机制损害健康。我们最近发现了Duper，一种 仓鼠突变，加快了昼夜节律，并显著加速了 光转移时的行为节律：黑暗循环。DUPER突变不是编码的改变 酪蛋白激酶区域或任何其他已知的时钟基因，似乎不影响转录- 翻译反馈环负责细胞自主振荡。我们会确认变种人的身份 等位基因的快速纯合性定位。我们将使用qRT-PCR来检测Duper等位基因对 心脏、肝脏、肾脏和心脏、肝脏和肾脏中核心时钟和时钟控制基因表达的昼夜相移 肌肉。鉴于对新陈代谢功能至关重要的基因转录受多个时钟控制 蛋白质或时钟依赖的转录因子，我们将使用RNA-Seq来揭示其程度 在轮班期间发生在器官内的转录组范围的阶段中断。我们将使用 免疫细胞化学检测DUPER对局部SCN功能的影响及其影响因素 起搏器与外周振荡器对重新夹带的潜伏期。最后，我们将测试 昼夜节律内部去同步化是扩张性心脏病加重的假说 在一个常用的仓鼠模型中，反复相移引起的心肌病。 仓鼠已被证明在研究生物节律方面很有价值，它们提供了一种独特的工具来 了解心脏病。排卵前黄体生成素高峰的昼夜节律控制在这一点上是很清楚的。 并为下丘脑起搏器控制从属振荡器提供了一个模型。我们的 这项工作将阐明昼夜节律不同步的机制，并使我们能够测试其在疾病中的作用。 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 心脏和肺的病理基础以及肝脏和肾脏的变化 会导致高血压和纤维化。研究结果也将有助于揭示睡眠不足的原因。 和代谢紊乱，并可能导致新的治疗方法的开发，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.