Role of Ror proteins in the mammalian circadian clock

Ror 蛋白在哺乳动物生物钟中的作用

• 批准号: 7533001
• 负责人: STEVE A KAY
• 金额: $ 12.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533001
• 关键词: Address; Affect; Behavior; Bioluminescence; Cells; Characteristics; Circadian Rhythms; Clinical; Crying; Cues; Data; Diagnostic; Disease; Event; Fatigue; Feedback; Genes; Genetic; Genetic Transcription; Goals; Heterogeneity; Incidence; Jet Lag Syndrome; Length; Limb structure; Liver; Luciferases; Malignant Neoplasms; Mammals; Molecular; Mus; Myocardial Infarction; Nuclear Orphan Receptor; Output; Peripheral; Phenotype; Physiological; Physiological Processes; Physiology; Play; Principal Investigator; Proteins; RNA Interference; Reporter; Resolution; Role; Seasonal Affective Disorder; Sleep Disorders; Specificity; Stroke; Subfamily lentivirinae; Systems Biology; Technology; Testing; Therapeutic; Time; Tissues; Transcription Coactivator; base; cellular imaging; circadian pacemaker; functional genomics; gene discovery; nervous system disorder; novel; programs; response

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.

该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到 内源时钟。生物钟机制由两个自动调节反馈回路组成， PER/CRY 核心循环和 BMAL1 互锁循环。在核心循环中，激活器 BMAL1 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 通过与 BMAL1/CLOCK 直接相互作用进行转录。最近的实验证据表明 第二个互锁 BMAL1 环作为稳定机制，有助于增强 生物钟。对于 BmaM 的节律表达，REV-ERBa 可以抑制 BmaM 转录。 我们的基因发现计划最近生成的数据表明 RORa 是一个积极的驱动因素 激活 SCN 中的小表达。 SCN 中的中央时钟集成了环境线索和 协调周围组织中的振荡器。我们建议定义相关蛋白 RORc 在 外周昼夜节律振荡器。我们将进一步扩展对 ROR 和 REV-ERB 的研究，以解决 他们各自对 BmaM 循环的贡献。这将作为探索的新切入点 SCN 和外设时钟的异质性和不同功能。最后我们重点关注肝脏 振荡器来解决肝脏发条如何参与局部生理过程。更好的 对昼夜节律时钟装置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 预计将完善诊断和治疗策略并揭示新的与时钟相关的 失调。目前，这些包括睡眠障碍、轮班工人疲劳、时差、癌症、心肌病 梗塞和中风、神经系统疾病和季节性抑郁症。