BMAL1 Complexes of the Circadian Clock

昼夜节律钟的 BMAL1 复合体

• 批准号: 8303353
• 负责人: CHARLES J WEITZ
• 金额: $ 39.62万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303353
• 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

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（申请人提供）：昼夜节律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一个转录反馈环建立的，该反馈环在分子水平上产生昼夜节律。二聚体转录因子CLOCK-BMAL 1是这个反馈环的核心，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特定过程知之甚少，这可以说是时钟机制的定义特征。 本申请提出了生物化学纯化和质谱法，以尽可能全面地鉴定与BMAL 1复合的蛋白质。将检测来自质谱法的候选物与来自多种组织的BMAL 1的免疫共沉淀。然后将在已建立的范例中研究确认的BMAL 1相关蛋白，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，则在分子方面这种作用的性质。BMAL 1复合物的许多蛋白质成分可能具有已知的功能，可能为时钟核心的分子事件提供新的线索。 该项目旨在确定在昼夜节律反馈回路中发挥重要但未被识别的作用的蛋白质，无论是在CLOCK-BMAL 1转录作用还是在CLOCK-BMAL 1转录活性的反馈抑制中。如果目标得以实现，该项目有可能扩大和加深我们对哺乳动物生物钟的了解，可能会朝着意想不到的方向发展。 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，进食行为异常和代谢综合征，如早期糖尿病。如果成功，这项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。