Regulation and Significance of Sustained Circadian Oscillations

描述(申请人提供)：昼夜节律是人类健康的重要组成部分，调节睡眠、警觉、荷尔蒙、新陈代谢和许多其他生物过程。这一现象的魅力在于解释了生化机制(I)如何强劲地维持长周期(~24小时)振荡，其频率如此精确地保持时间，以及(Ii)增强在自然环境中的适应性。这些问题在昼夜节律领域仍然是极其重要的悬而未决的问题。例如，对于最明显的昼夜节律特征--恒定条件下稳健的自我维持振荡--的适应性并不清楚。如果对未来时间事件(如黎明、黄昏等)的“预期”生物钟计时员的目标是什么？为什么在黎明或黄昏启动的温度补偿的“沙漏计时器”是不够的？然而，在每一种情况下，进化都选择了一种非自然连续地维持自身的振荡器作为调节日常过程的计时器，这一特征形成了昼夜节律的核心定义因素。的总体假设 这个项目是，在恒定环境中自我维持的昼夜节律起搏器确实在周期性环境中提供了适应优势，并且多振荡器结构有助于维持体内的高幅度振荡。检验这一假说将利用真细菌细长聚球藻(蓝藻)和大肠杆菌的独特能力，从遗传、生化和适应性测试三个方面入手。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“标志”。其次，将评估多振荡器组织的贡献，以建立(I)稳健的、自我持续的振荡，以及(Ii)适应性竞争力。最后，一种新的实验选择方法将确定可能导致自我维持的昼夜振荡演变的环境压力。这些问题的答案将有助于我们理解新陈代谢的基本昼夜节律组织和节律调节；这种理解可以帮助我们更好地设计治疗与生物钟有关的疾病的方法。

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.