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（每日）节律是调节睡眠、警觉性、激素、代谢和许多其他生物过程的人类健康的重要组成部分。这一现象的魅力在于解释生物化学机制如何（i）能够稳健地维持长时间（~24小时）振荡，其频率如此精确地保持时间，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未回答的问题。例如，对于最明显的昼夜节律特征--在恒定条件下的稳健的自我维持振荡，适应性尚不清楚。如果对未来时间事件的“预期”（例如，黎明、黄昏等）是昼夜节律计时器的目标，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，在每一种情况下，进化都选择了一个振荡器，它以非自然的连续性维持自己，作为调节日常过程的计时器，而这个特征形成了昼夜节律的核心定义因素。总体假设 这个项目是在恒定环境中自我维持的昼夜节律起搏器在周期性环境中确实提供了适应性优势，并且多振荡器结构有助于维持体内的高振幅振荡。 检验这一假设将利用真细菌细长聚球藻（蓝细菌）和大肠杆菌的独特能力。通过三管齐下的方法--遗传的、生化的和适应性的测试，首先，持续的昼夜节律振荡的适应值将通过竞争测定来量化，并且与适应性相关的代谢模式将被识别为由持续的昼夜节律振荡赋予的优势的“签名”。第二，多振荡器组织的贡献将被评估，以建立（i）强大的，自我维持的振荡，（ii）适应性竞争力。最后，一种新的实验选择方法将确定环境压力，可以导致自我维持的昼夜节律振荡的演变。 这些问题的答案将有助于我们理解基本的昼夜节律组织和代谢的节律调节;这种理解可以帮助我们更好地设计涉及昼夜节律钟的疾病的治疗方法。