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: 7204152
• 负责人: STEVE A KAY
• 金额: $ 36.75万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2007-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7204152
• 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

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.

描述（由申请人提供）：该提案涉及哺乳动物中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含昼夜振荡器的组件的功能和组织特异性。在哺乳动物中，生理和行为方面的昼夜节律由内源性时钟调节。昼夜节律时钟机制包括两个自动调节反馈回路，每/哭泣的核心环和BMAL1互锁环。在核心循环中，激活剂BMAL1和时钟激活Per和Cry基因的转录； PER和哭泣的蛋白质反过来又通过与BMAL1/Clock的直接相互作用来阻止其自己的转录。最近的实验证据表明，第二连锁BMAL1环路是稳定机制，有助于昼夜节律的稳健性。对于BMAM的节奏表达，Rev-Erba起作用抑制BMAM转录。我们的基因发现程序最近生成了数据，以表明RORA是激活SCN中小表达的积极驱动因素。 SCN中的中心时钟整合了环境线索，并在外围组织中坐标振荡器。我们建议定义相关蛋白RORC在外围昼夜节律振荡器中的作用。我们将进一步扩展有关RORS和REV-ERB的研究，以解决它们对BMAM循环的各自贡献。这将是探索SCN和外围时钟的异质性和不同功能的新入口处。最后，我们将专注于肝振荡器，以解决肝发条如何参与局部生理过程。更好地了解昼夜节律的发条和外围振荡器，将扩展我们对临床事件发生率和治疗反应的昼夜变化的机制的理解。这将有望完善诊断和治疗策略，并揭示与时钟相关的新型疾病。目前，其中包括睡眠障碍，班次工人疲劳，喷气滞后，癌症，心肌梗塞和中风，神经系统疾病和季节性抑郁症。