Role of Ror proteins in the mammalian circadian clock

描述（由申请人提供）：本提案涉及哺乳动物昼夜节律的组成和控制。我们的目标是在分子和细胞水平上了解组成昼夜节律振荡器的组件的功能和组织特异性。在哺乳动物中，生理和行为的昼夜节律由内源性时钟调节。生物钟机制由两个自动调节反馈回路组成，PER/CRY核心回路和BMAL 1联锁回路。在核心环中，激活子BMAL 1和CLOCK激活Per和Cry基因的转录; PER和Cry蛋白反过来通过与BMAL 1/CLOCK的直接相互作用抑制它们自己的转录。最近的实验证据表明，第二个联锁BMAL 1环作为一种稳定机制，有助于生物钟的鲁棒性。对于BmaM的节律性表达，REV-ERBa起到抑制BmaM转录的作用。我们的基因发现计划最近产生的数据表明，RORa作为一个积极的驱动程序，激活小表达的SCN。SCN中的中央时钟整合环境线索并协调外周组织中的振荡器。我们建议定义相关蛋白RORc在外周昼夜节律振荡器中的作用。我们将进一步扩展对ROR和REV-ERB的研究，以解决它们各自对BmaM回路的贡献。这将作为一个新的切入点，探索SCN和外围时钟的异质性和不同的功能。最后，我们将集中在肝脏振荡器，以解决如何肝脏时钟参与当地的生理过程。更好地了解昼夜时钟和周边振荡器，将扩大我们的理解的机制，昼夜变化的发生率的临床事件和治疗反应。这将有望完善诊断和治疗策略，并揭示新的生物钟相关疾病。目前，这些包括睡眠障碍，轮班工人疲劳，时差，癌症，心肌梗死和中风，神经系统疾病和季节性抑郁症。

DESCRIPTION (provided by applicant): This proposal concerns the composition and control of circadian rhythms in mammals. Our goal is to understand at the molecular and cellular level the function and tissue specificity of components comprising the circadian oscillator. In mammals, circadian rhythms in physiology and behavior are regulated by an endogenous clock. The circadian clock mechanism consists of two autoregulatory feedback loops, the PER/CRY core loop and the BMAL1 interlocking loop. In the core loop, the activators BMAL1 and CLOCK activate the transcription of Per and Cry genes; PER and CRY proteins in turn repress their own transcription through direct interaction with BMAL1/CLOCK. Recent experimental evidence suggested that a second interlocking BMAL1 loop serves as a stabilizing mechanism that contributes to the robustness of the circadian clock. For the rhythmic expression of BmaM, REV-ERBa acts to repress BmaM transcription. Our gene discovery program recently generated data to show that RORa acts as a positive driver to activate Small expression in the SCN. The central clock in the SCN integrates environmental cues and coordinates oscillators in peripheral tissues. We propose to define the role of the related protein RORc in peripheral circadian oscillators. We will further extend the study on the RORs and REV-ERBs to address their respective contributions to the BmaM loop. This will serve as a new entry point to explore the heterogeneity and distinct functions of the SCN and peripheral clocks. Finally we will focus on the liver oscillator to address how the liver clockworks participate in local physiological processes. Better understanding of the circadian clockworks and peripheral oscillators, will expand our understanding of the mechanisms that underlie diurnal variation in the incidence of clinical events and therapeutic response. This would be expected to refine diagnostic and therapeutic strategies and to reveal novel clock-related disorders. Presently, these include sleep disorders, shift-worker fatigue, jet lag, cancer, myocardial infarction and stroke, neurological disorders, and seasonal depression.