Role of Ror proteins in the mammalian circadian clock

这一提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理解组分的功能和组织特异性，包括 昼夜节律振荡器在哺乳动物中，生理和行为的昼夜节律是由一种 内源性时钟生物钟机制由两个自动调节反馈回路组成， PER/CRY核心环路和BMAL 1联锁环路。在核心循环中，激活器BMAL 1和CLOCK 激活Per和Cry基因的转录; PER和CRY蛋白反过来抑制它们自己的转录， 通过与BMAL 1/CLOCK的直接相互作用进行转录。最近的实验证据表明， 第二个互锁BMAL 1环用作稳定机制，有助于 生物钟对于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生成的数据表明，RORa作为一个积极的驱动程序， 激活SCN中的Small表达。SCN中的中央时钟整合了环境线索， 协调周围组织中的振荡器。我们建议定义相关蛋白RORc在 外周昼夜节律振荡器我们会进一步扩展有关认可评级及修订再培训局的研究， 它们各自对BmaM循环的贡献。这将作为一个新的切入点， SCN和外围时钟的异质性和不同功能。最后，我们将关注肝脏 振荡器来解决肝脏时钟如何参与局部生理过程。更好 了解昼夜节律时钟和外围振荡器，将扩大我们的理解 临床事件和治疗反应发生率昼夜变化的基础机制。这 将有望完善诊断和治疗策略，并揭示新的生物钟相关的 紊乱目前，这些包括睡眠障碍，轮班工人疲劳，时差，癌症，心肌 梗塞和中风、神经系统疾病和季节性抑郁症。

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.