Regulation and Significance of Sustained Circadian Oscillations

持续昼夜节律振荡的调节和意义

• 批准号: 8562033
• 负责人: CARL Hirschie JOHNSON
• 金额: $ 29.29万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8562033
• 关键词: Address; Anguish; Bacteria; Biochemical; Biochemical Reaction; Bioinformatics; Biological; Biological Assay; Biological Clocks; Biological Models; Biological Process; Cardiovascular Diseases; Characteristics; Circadian Rhythms; Coupled; Cyanobacterium; Disease; Environment; Escherichia coli; Eubacterium; Event; Evolution; Exhibits; Financial compensation; Frequencies; Future; Gene Expression Profile; Genetic; Genomics; Goals; Health; Hour; Human; Jet Lag Syndrome; Lead; Light; Maintenance; Malignant Neoplasms; Mental Depression; Mental Health; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mutation; Noise; Organism; Pattern; Performance; Periodicity; Personal Satisfaction; Phase; Phenotype; Plants; Process; Property; Protocols documentation; Regulation; Schedule; Sleep; Staging; Structure; Synechococcus; System; Temperature; Testing; Time; alertness; circadian pacemaker; fitness; fungus; hormone metabolism; in vivo; novel; peroxiredoxin; physical conditioning; pressure; public health relevance; research study; response; therapy design; therapy development

DESCRIPTION (provided by applicant): Circadian (daily) rhythms are a crucial component of human health that regulates sleep, alertness, hormones, metabolism, and many other biological processes. The fascination of this phenomenon is to explain how a biochemical mechanism (i) can robustly sustain a long period (~24 h) oscillation whose frequency keeps time so precisely, and (ii) enhance fitness in the natural environment. These questions remain critically important unanswered issues in the circadian rhythms field. For example, the adaptiveness is not clear for the most obvious circadian characteristic-a robust self-sustained oscillation in constant conditions. If "anticipation" of future temporal events (e.g., dawn, dusk, etc.) is the goal of circadian timekeepers, why is a temperature-compensated "hourglass timer" that is initiated by dawn or dusk not sufficient? And yet evolution in every case has selected an oscillator that sustains itself in non-natural continuous as the timekeeper for regulating daily processes, and this characteristic forms the core defining factor for circadian rhythms. The overall hypothesis of this project is that circadian pacemakers that are self-sustained in constant environments do provide a fitness advantage in cyclic environments and that multioscillator structure contributes to the maintenance of high amplitude oscillations in vivo. Testing this hypothesis will take advantage of the unique capabilities of the eubacteria Synechococcus elongatus (cyanobacterium) and E. coli by a three-pronged approach-genetic, biochemical, and by tests of adaptive fitness. First, the adaptive value of sustained circadian oscillations will be quantified y competition assays and metabolic patterns that correlate with adaptiveness will be identified as a "signature" of the advantage conferred by sustained circadian oscillations. Second, the contributions of multioscillator organization will be assessed towards establishing (i) robust, sel-sustained oscillations, and (ii) adaptive competitiveness. Finally, a novel experimental selection approach will identify environmental pressures that can lead to the evolution of self-sustained circadian oscillations. The answers to these questions will help us to understand fundamental circadian organization and rhythmic regulation of metabolism; this understanding can help us to better design therapies for disorders in which circadian clocks are implicated.

描述（由申请人提供）：昼夜节律（每日）节律是人类健康的重要组成部分，它调节睡眠、警觉性、激素、新陈代谢和许多其他生物过程。这种现象的魅力在于解释生化机制如何（i）能够稳健地维持长时间（约 24 小时）振荡，其频率使时间保持如此精确，以及（ii）增强自然环境中的适应性。这些问题在昼夜节律领域仍然是至关重要的尚未解答的问题。例如，对于最明显的昼夜节律特征——恒定条件下的鲁棒自我维持振荡——的适应性并不明确。如果“预期”未来的时间事件（例如黎明、黄昏等）是昼夜节律计时器的目标，那么为什么由黎明或黄昏启动的温度补偿“沙漏计时器”还不够呢？然而，在每种情况下，进化都选择了一个以非自然连续方式维持自身的振荡器作为调节日常过程的计时器，而这一特性构成了昼夜节律的核心决定因素。总体假设为 该项目的重点是，在恒定环境中自我维持的昼夜节律起搏器确实在循环环境中提供了适应性优势，并且多振荡器结构有助于维持体内高振幅振荡。 检验这一假设将通过三管齐下的方法——遗传、生化和适应性适应性测试，利用真细菌细长聚球藻（蓝细菌）和大肠杆菌的独特能力。首先，持续昼夜节律振荡的适应性价值将通过竞争分析进行量化，与适应性相关的代谢模式将被识别为持续昼夜节律振荡所赋予的优势的“特征”。其次，将评估多振荡组织的贡献，以建立（i）稳健的、自我维持的振荡，以及（ii）适应性竞争力。最后，一种新颖的实验选择方法将识别可能导致自我维持昼夜节律振荡进化的环境压力。 这些问题的答案将帮助我们了解基本的昼夜节律组织和新陈代谢的节律调节；这种理解可以帮助我们更好地设计针对与生物钟有关的疾病的治疗方法。