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BMAL1 Complexes of the Circadian Clock

昼夜节律钟的 BMAL1 复合体

基本信息

批准号：
8656710
负责人：
CHARLES J WEITZ
金额：
$ 39.74万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8656710
关键词：
Affinity Chromatography BMAL1 protein Behavior Behavior Control Behavioral Biochemical Biological Biological Pacemakers Biological Process Brain Circadian Rhythms Co-Immunoprecipitations Complex Defect Diabetes Mellitus Diagnosis Disease Elements Event Feedback Feeding behaviors Functional disorder General Transcription Factors Genetic Goals Health Health Hazards Heart Human Investigation Knowledge Lead Link Mammals Mass Spectrum Analysis Mediator of activation protein Metabolic Metabolic syndrome Metabolism Molecular Molecular Genetics Mus Nature Obesity Peripheral Phase Physiological Physiology Play Process Protein Kinase C Proteins Publishing Role Science Sleep Sleep Disorders Sleep Wake Cycle Staging System Testing Time Tissues Work circadian pacemaker global health improved insight loss of function novel programs protein complex receptors for activated C kinase transcription factor

项目摘要

DESCRIPTION (provided by applicant): Circadian clocks are endogenous oscillators that drive daily rhythms of biological processes. In mammals, circadian clocks are found in the brain and in most peripheral tissues. Distributed clocks appear to constitute a fundamental timing system that coordinates behavior and physiology. The mammalian clock is built from a transcriptional feedback loop that generates circadian rhythms at the molecular level. The dimeric transcription factor CLOCK- BMAL1 is at the heart of this feedback loop, but surprisingly little is known about its mechanism of transcriptional action or the specific processes causing its negative feedback suppression, arguably the defining feature of the clock mechanism. This application proposes biochemical purification and mass spectrometry to identify, comprehensively if possible, the proteins in a complex with BMAL1. Candidates from mass spectrometry will be tested for co-immunoprecipitation with BMAL1 from multiple tissues. Confirmed BMAL1-associated proteins will then be studied in established paradigms, including loss-of-function studies, to determine if they play a role in circadian oscillations and, if so, the nature of that role in molecular terms. It is likely that many of the protein constituents of BMAL1 complexes have known functions, potentially offering novel clues to molecular events at the core of the clock. The project aims to identify proteins playing an important but unrecognized role in the circadian feedback loop, either in CLOCK-BMAL1 transcriptional action or in feedback suppression of CLOCK-BMAL1 transcriptional activity. If the aims are achieved, the project has the potential to expand and deepen our knowledge of the mammalian clock, possibly in unanticipated directions. Advances in understanding the mammalian circadian clock will have important implications for our view of the genetic control of behavior and physiology, as well as for human health and disease. Mouse genetic studies indicate that defects of clock function lead to broad behavioral and metabolic dysfunction, producing, for example, disrupted sleep-wake cycles, abnormal feeding behavior, and a metabolic syndrome like early-stage diabetes. If successful, the proposed study could provide new insight into genetic and molecular mechanisms controlling behavioral and physiological programs.

描述（由申请人提供）：生物钟是驱动生物过程每日节律的内源性振荡器。在哺乳动物中，生物钟存在于大脑和大多数外周组织中。分布式时钟似乎构成了一个协调行为和生理的基本计时系统。哺乳动物的生物钟是由转录反馈回路构建的，该回路在分子水平上产生昼夜节律。二聚体转录因子CLOCK- BMAL1是这种反馈回路的核心，但令人惊讶的是，人们对其转录作用机制或导致其负反馈抑制的具体过程知之甚少，而负反馈抑制可能是时钟机制的定义特征。本应用程序提出生化纯化和质谱法，以确定，如果可能的话，全面的蛋白质与BMAL1复合物。质谱候选物将与来自多个组织的BMAL1进行共免疫沉淀测试。确认的bmal1相关蛋白将在已建立的范例中进行研究，包括功能丧失研究，以确定它们是否在昼夜节律振荡中发挥作用，如果是的话，从分子角度确定这种作用的性质。很可能BMAL1复合体的许多蛋白质成分都有已知的功能，可能为生物钟核心的分子事件提供新的线索。该项目旨在确定在生物钟反馈回路中发挥重要但未被认识到的作用的蛋白质，无论是在CLOCK-BMAL1转录作用中，还是在CLOCK-BMAL1转录活性的反馈抑制中。如果目标实现，该项目有可能扩大和深化我们对哺乳动物生物钟的认识，可能是在意想不到的方向上。了解哺乳动物生物钟的进展将对我们对行为和生理的遗传控制以及人类健康和疾病的看法产生重要影响。小鼠遗传学研究表明，生物钟功能的缺陷会导致广泛的行为和代谢功能障碍，例如，睡眠-觉醒周期中断，进食行为异常，以及像早期糖尿病这样的代谢综合征。如果成功，该研究将为控制行为和生理程序的遗传和分子机制提供新的见解。