Role of Ror proteins in the mammalian circadian clock

这项建议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包括以下成分的功能和组织特异性 昼夜节律振荡器。在哺乳动物中，生理和行为的昼夜节律受 内生钟。生物钟机制由两个自动调节反馈环路组成， PER/CRY核心环路和BMAL1联锁环路。在核心环路中，激活器BMAL1和时钟 激活Per和Cry基因的转录；Per和Cry蛋白反过来抑制自己的基因 通过与BMAL1/CLOCK直接相互作用转录。最近的实验证据表明 第二个联锁BMAL1环路用作稳定机制，有助于 生物钟。对于BmaM的节律性表达，REV-ERBA具有抑制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是一个积极的驱动因素 激活SCN中的小表达。SCN中的中央时钟整合了环境线索和 协调周围组织中的振荡器。我们建议定义相关蛋白RORC在 外围昼夜节律振荡器。我们会进一步扩大对资源需求和资源需求报告的研究，以解决 他们各自对BMAM循环的贡献。这将作为一个新的切入点来探索 SCN和外设时钟的异质性和不同的功能。最后，我们将重点介绍肝脏 振荡器，以解决肝脏时钟如何参与局部生理过程。更好 对生物钟和外围振荡器的了解，将扩大我们对 临床事件发生率和治疗反应的昼夜变化的机制。这 将有望改进诊断和治疗策略，并揭示与时钟相关的新技术 精神错乱。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 脑梗塞和中风、神经紊乱和季节性抑郁症。

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.