Circadian Rhythms and Internal Desynchronization

昼夜节律和内部不同步

基本信息

批准号：
9752371
负责人：
ERIC L BITTMAN
金额：
$ 71.61万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752371
关键词：
Affect Alleles American Animals Arousal Behavior Behavioral Biological Rhythm Brain Businesses Cardiomyopathies Cardiovascular Physiology Cardiovascular system Cells Circadian Dysregulation Circadian Rhythms Circadian desynchrony Clock protein Code Complex Coupling Deterioration Development Dilated Cardiomyopathy Disease Disease Progression Dystrophin Event Feedback Fibroblasts Fibrosis Gene Expression Genes Genetic Genetic Transcription Hamsters Health Heart Heart Diseases Human Hypertension Hypothalamic structure Jet Lag Syndrome Kidney Lead Light Liver Longevity Lung Mediating Mesocricetus auratus Metabolic Metabolic Diseases Metabolism Modeling Molecular Morbidity - disease rate Muscle Mutation Neurologic Process Neurosecretory Systems Occupations Organ Pacemakers Pathology Peripheral Phase Physiological Physiology Process Quantitative Reverse Transcriptase PCR Regulatory Element Research Rest Role Schedule Signal Transduction Sleep Sleep Deprivation Speed Testing Therapeutic Time Tissues Transcript Work casein kinase cell type circadian circadian pacemaker delta Sarcoglycan experience experimental study heart function immunocytochemistry improved mortality mutant novel novel therapeutics pleasure relating to nervous system shift work social suprachiasmatic nucleus tool transcription factor transcriptome transcriptome sequencing

项目摘要

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.

摘要/项目摘要下丘脑视交叉上核中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受环境控制信号，主要是光。昼夜节律组织的破坏，例如发生在轮班工作和时差反应中，通过人们知之甚少的机制损害健康。我们最近发现了 duper，一个仓鼠突变加快了生物钟并显着加速了光：暗周期转变时的行为节律。 duper 突变并不是编码的改变酪蛋白激酶或任何其他已知时钟基因的区域，并且似乎不影响转录- 负责细胞自主振荡的平移反馈回路。我们将识别突变体等位基因通过快速纯合性作图。我们将使用 qRT-PCR 来检查 duper 等位基因对心脏、肝脏、肾脏和心脏中核心时钟和时钟控制基因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 来揭示轮班期间器官内发生的转录组范围内的相位破坏。我们将使用免疫细胞化学检查 duper 对区域 SCN 功能的影响，并分析其贡献起搏器与外周振荡器对重新夹带延迟的影响。最后，我们将测试假设昼夜节律的内部不同步是导致扩张加剧的原因在常用的仓鼠模型中通过重复相移来治疗心肌病。事实证明，仓鼠在生物节律研究中很有价值，它们为研究生物节律提供了独特的工具。了解心脏病。排卵前 LH 激增的昼夜节律控制在这方面已得到充分理解种并提供了下丘脑起搏器控制从属振荡器的模型。我们的这项工作将揭示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。鉴于昼夜节律组织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。