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昼夜节律振荡器组成部分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是由内源性时钟调节的。生物钟机制由两个自调节反馈回路组成，即PER/CRY核心回路和BMAL1互锁回路。在核心环中，激活因子BMAL1和CLOCK激活Per和Cry基因的转录；PER和CRY蛋白反过来通过与BMAL1/CLOCK的直接相互作用抑制自身的转录。最近的实验证据表明，第二个互锁的BMAL1环作为一种稳定机制，有助于生物钟的稳健性。REV-ERBa对BmaM的节律性表达起抑制作用。我们的基因发现项目最近产生的数据表明，RORa是激活SCN中Small表达的积极驱动因素。SCN中的中央时钟整合周围组织的环境信号和协调振荡器。我们建议确定相关蛋白RORc在外周昼夜节律振荡器中的作用。我们会进一步扩展对RORs和rev - erb的研究，以探讨它们各自对BmaM循环的贡献。这将为探索SCN和外周时钟的异质性和不同功能提供一个新的切入点。最后，我们将关注肝脏振荡器，以解决肝脏时钟如何参与局部生理过程。更好地了解生物钟和外周振荡器，将扩大我们对临床事件和治疗反应发生率日变化的机制的理解。这将有望完善诊断和治疗策略，并揭示新的时钟相关疾病。目前，这些疾病包括睡眠障碍、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.