Regulation and Significance of Sustained Circadian Oscillations

持续昼夜节律振荡的调节和意义

• 批准号: 9381730
• 负责人: CARL Hirschie JOHNSON
• 金额: $ 30.61万
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381730
• 关键词: Address; Aerobic; Alpha Rhythm; Bacteria; Bacterial Model; Biochemical; Biochemical Reaction; Biochemistry; Bioinformatics; Biological; Biological Clocks; Biological Models; Biological Process; Cardiovascular Diseases; Characteristics; Circadian Rhythms; Clock protein; Complex; Coupled; Darkness; Dimensions; Disease; Environment; Environmental Risk Factor; Escherichia coli; Event; Evolution; Feeding Patterns; Financial compensation; Frequencies; Future; Gene Expression; Gene Expression Regulation; Gene Structure; Genes; Genetic; Genomics; Goals; Health; Hour; Human; Jet Lag Syndrome; Lead; Light; Malignant Neoplasms; Mental Depression; Mental Health; Mental disorders; Metabolic; Metabolic Diseases; Metabolism; Molds; Molecular; Mutation; Natural Selections; Organism; Pattern; Performance; Periodicity; Phase; Process; Property; Proteins; Protocols documentation; Public Health; Regulation; Role; Schedule; Sleep; System; Temperature; Testing; Time; Variant; alertness; circadian pacemaker; fascinate; fitness; fitness test; gut microbiome; hormone metabolism; improved; microbial community; microbiome; novel; physical conditioning; pressure; progenitor; response; shift work; therapy design; therapy development; transcriptome; transcriptomics

Project Summary/Abstract: 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 adaptive value 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 ubiquitously selected an oscillator that sustains itself in non-natural continuous as the timekeeper for regulating daily processes, and this characteristic forms a core defining property of circadian rhythms. The overall goal of this project is to determine which characteristics of rhythmic environments provide selective pressures that direct cellular organization of gene expression and metabolism to promote properties of circadian timekeeping. Identifying the selective pressures & evolutionary steps that can lead to biological timekeeping will enable a more profound understanding of circadian mechanisms and the way(s) they might be reinforced to aid human health and performance. The unique characteristics of model systems will be harnessed to attain the goal of this project by a multifaceted approach. First, in free-living organisms, fitness tests, transcriptomics, and biochemistry will determine if metabolic conditions dictate whether sustained oscillators are necessarily adaptive. Second, the temporal dimensions of host/microbiome relations will be manipulated to ascertain if the gut microbiome is under active selection for timekeeping ability. Finally, a novel experimental selection approach will identify which environmental pressures are capable of evolving circadian clocks. The answers to these questions will help us to better understand general principles of 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.

项目摘要/摘要： 昼夜节律（每日）节律是调节睡眠的人类健康的重要组成部分， 警觉性、激素、新陈代谢和许多其他生物过程。这一切的魅力 现象是为了解释生化机制（i）如何能够稳健地维持很长一段时间 (~24 小时) 振荡，其频率如此精确地保持时间，并且 (ii) 增强身体的适应性 自然环境。这些问题仍然是至关重要的尚未解答的问题 昼夜节律场。例如，对于最明显的自适应值并不明确 昼夜节律特征——在恒定条件下强大的自我维持振荡。如果“期待” 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，为什么 在黎明或黄昏启动的温度补偿“沙漏计时器”还不够吗？和 然而进化无处不在地选择了一个以非自然连续的方式维持自身的振荡器 调节日常流程的计时器，这一特征构成了核心定义 昼夜节律的特性。该项目的总体目标是确定哪些 节律性环境的特征提供了指导细胞的选择压力 组织基因表达和代谢以促进昼夜节律特性 计时。识别可能导致生物进化的选择压力和进化步骤 计时将使人们更深刻地了解昼夜节律机制和 可以通过哪些方式加强它们以帮助人类健康和提高表现。 将利用模型系统的独特特征来实现这一目标 通过多方面的方法进行项目。首先，在自由生活的有机体、适应性测试、转录组学中， 生物化学将决定代谢条件是否决定持续振荡器是否有效 必然具有适应性。其次，宿主/微生物组关系的时间维度将是 进行操作以确定肠道微生物组是否处于计时能力的主动选择之下。 最后，一种新颖的实验选择方法将确定哪些环境压力是 能够进化生物钟。 这些问题的答案将帮助我们更好地理解一般原则 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。