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Molecular, Cellular and Physiological Mechanisms of the Mammalian Circadian Clock

哺乳动物昼夜节律钟的分子、细胞和生理机制

基本信息

批准号：
7591666
负责人：
JOHN B HOGENESCH
金额：
$ 51万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591666
关键词：
Address Alleles Animal Model Animals Biochemical Biological Assay Body Weight Cell Nucleus Cells Circadian Rhythms Complex Crying Dose Energy Metabolism Fatty acid glycerol esters Feedback Food Foundations Generations Genes Genetic Genetic Transcription Histone Acetylation Homebound Persons Hour In Vitro Indirect Calorimetry Knock-in Mouse Knock-out Lipids Maintenance Mammalian Cell Measures Mediating Metabolic Metabolism Methylation Modeling Modification Molecular Molecular Genetics Monitor Motor Activity Mus Peripheral Physiological Physiology Play Post-Translational Protein Processing Proteins Proteomics Regulation Repression Research Research Personnel Resistance Role Screening procedure Serum Site Sleep Wake Cycle Testing Trans-Activators Transcription Repressor/Corepressor Translating Water consumption Weaning Work base casein kinase I chromatin remodeling circadian pacemaker cryptochrome cryptochrome 1 cryptochrome 2 in vivo inhibitor/antagonist mouse model mutant positional cloning programs pup restoration small molecule stoichiometry tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The circadian clock is thought to coordinate aspects of mammalian physiology such as metabolism and the sleep wake cycle. Genetic and molecular characterization of the circadian oscillator shows that interlocked transcriptional/translational feedback loops underlie these rhythms. Recent findings have reinforced the notion that the primary feedback loop plays a vital role in circadian clock function. In this loop, two bHLH-PAS transactivators, Clock and Bmall, heterodimerize and stimulate circadian expression of two potent transcriptional repressors, Cryptochrome 1 and Cryptochrome 2. Once translated, Cry proteins then form a complex with the Period and casein kinase 1 proteins, and translocate to the nucleus where they potently represses Clock/Bmall transcription. This results in the shut down of Cry gene transcription, which eventually results in 'de-repression' of the Clock/BmaM complex and re-initiation of the transcriptional cycle after -24 hours. Although changes in chromatin remodeling and histone acetylation and methylation have been observed to accompany Cry protein repression activity, the molecular mechanism by which Cry proteins act to repress the Clock/Bmall complex remains to be elucidated. Here we propose molecular, cellular, and physiological characterization of the mechanisms underlying clock function including Cry repression. Furthermore, we propose generation of a mouse model that is uncoupled from Cry-mediated feedback repression (a circadian clock knockout) and use this model to investigate the hypothesis that circadian oscillation, rather than the specific clock factors Clock and Bmall, is required to maintain normal metabolic function. Finally, we propose a mechanism-based strategy to identify and characterize small molecules with the capacity to perturb oscillator function via effects on the negative feedback loop. Thus successful completion of the proposed research would result in an important animal model for ascribing circadian clock function in physiology, as well as lay the foundation for mechanism based small molecule perturbation of the clock.

描述（由申请人提供）：生物钟被认为可以协调哺乳动物生理学的各个方面，例如新陈代谢和睡眠觉醒周期。昼夜节律振荡器的遗传和分子特征表明，互锁的转录/翻译反馈环是这些节律的基础。最近的研究结果强化了这样的观点，即主反馈回路在生物钟功能中起着至关重要的作用。在此环中，两个 bHLH-PAS 反式激活因子 Clock 和 Bmall 异二聚化，并刺激两个有效转录抑制因子 Cryptochrome 1 和 Cryptochrome 2 的昼夜节律表达。翻译后，Cry 蛋白随后与 period 和酪蛋白激酶 1 蛋白形成复合物，并易位到细胞核，在细胞核中有效抑制 Clock/Bmall 转录。这导致 Cry 基因转录关闭，最终导致 Clock/BmaM 复合物“去抑制”，并在 -24 小时后重新启动转录周期。尽管已观察到染色质重塑以及组蛋白乙酰化和甲基化的变化伴随着 Cry 蛋白抑制活性，但 Cry 蛋白抑制 Clock/Bmall 复合物的分子机制仍有待阐明。在这里，我们提出了包括哭声抑制在内的时钟功能机制的分子、细胞和生理学特征。此外，我们建议生成一种与 Cry 介导的反馈抑制（昼夜节律时钟敲除）分离的小鼠模型，并使用该模型来研究维持正常代谢功能需要昼夜节律振荡而不是特定时钟因子 Clock 和 Bmall 的假设。最后，我们提出了一种基于机制的策略来识别和表征小分子，这些小分子能够通过对负反馈回路的影响来扰乱振荡函数。因此，成功完成所提出的研究将产生一个重要的动物模型，用于在生理学中归因生物钟功能，并为基于机制的小分子扰动生物钟奠定基础。