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： 昼夜节律的节奏是调节睡眠的人类健康的关键组成部分 机敏，激素，代谢和许多其他生物学过程。迷恋 现象是要解释生化机制（i）如何坚固地维持长时间 （〜24 h）振荡的频率如此精确地保持时间，并且（ii）提高适合度 自然环境。这些问题仍然至关重要 昼夜节律领域。例如，最明显的自适应价值尚不清楚 昼夜节律特征 - 在恒定条件下稳健的自我维持的振荡。如果“期待” 未来的临时事件（例如，黎明，黄昏等）是昼夜节律的目标，为什么 由黎明或黄昏发起的温度补偿的“沙漏计时器”不够？和 然而，进化无处不在选择一种自杀以自杀的振荡器 控制日常过程的计时员，并且此特征形成了定义的核心 昼夜节律的财产。该项目的总体目标是确定哪个 节奏环境的特征提供了选择性的压力，可以直接细胞 组织基因表达和代谢以促进昼夜节律的特性 计时。确定可以导致生物学的选择性压力和进化步骤 计时将使人们能够对昼夜节律和 方式可能会得到加强以帮助人类的健康和绩效。 模型系统的独特特征将被利用以实现这一目标 通过多方面的方法进行项目。首先，在自由生活的生物中，健身测试，转录组学， 生物化学将确定代谢条件是否决定持续的振荡器是否是 一定是适应性的。其次，主机/微生物组关系的临时维度将是 操纵以确定肠道微生物组是否处于主动选择方面以获得计时能力。 最后，一种新型的实验选择方法将确定哪些环境压力是 能够不断发展的昼夜节律。 这些问题的答案将有助于我们更好地理解 基本的昼夜节律组织和代谢的节奏调节；这种理解 可以帮助我们更好地设计与昼夜节律有关的疾病的设计疗法。