Regulation and Significance of Sustained Circadian Oscillations

描述（由申请人提供）：昼夜节律是人类健康的重要组成部分，调节睡眠、警觉性、激素、新陈代谢和许多其他生物过程。这一现象的迷人之处在于，它解释了生化机制如何(1)能够稳定地维持长时间（~24小时）的振荡，其频率保持时间如此精确，以及(2)增强在自然环境中的适应性。这些问题仍然是昼夜节律领域中至关重要的未解之谜。例如，对于最明显的昼夜节律特征——在恒定条件下强劲的自我持续振荡——适应性并不清楚。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，为什么由黎明或黄昏启动的温度补偿“沙漏计时器”是不够的？然而，在每种情况下，进化都选择了一种振荡器，它以非自然的连续方式维持自己，作为调节日常过程的计时器，这种特征形成了昼夜节律的核心定义因素。的总体假设

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.