Regulation and Significance of Sustained Circadian Oscillations

项目概要/摘要 昼夜节律是人类健康的重要组成部分，它调节睡眠、警觉性， 稳态、细胞信号传导和许多其他生物过程。这种现象的魅力在于 解释生物化学机制（i）如何能够稳健地维持长周期（~24 h）振荡， 频率保持时间如此精确，和（ii）增强在自然环境中的适应性。这些问题仍然存在 昼夜节律领域中至关重要的未解问题。例如，自适应值不是 最明显的昼夜节律特征是在恒定条件下的强健的自我维持振荡。如果 未来时间事件的“预期”（例如，黎明、黄昏等）是昼夜节律计时员的目标，为什么 由黎明或黄昏启动的温度补偿“沙漏计时器”还不够吗？然而进化论 普遍选择了一种振荡器，在非自然连续条件下维持自己作为计时器， 调节日常过程，并且该特征形成了昼夜节律的核心定义性质。的 这个项目的总体目标是确定节奏环境的哪些特征提供选择性的 协调基因表达和信息处理的细胞组织的压力，以促进 昼夜节律计时的特性识别选择性压力和进化步骤，可能导致 生物计时将使人们能够更深刻地理解昼夜节律机制和信号， 它们可能被加强以帮助人类健康和表现。 模型系统的独特特性将通过以下方式来实现本项目的目标： 多方面的方法。首先，在自由生活的生物体中，季节性反应的昼夜节律调节， 将研究细胞群落内的昼夜节律相互作用，以确定为什么持续振荡器 必须适应。其次，将操纵宿主/微生物组关系的时间维度， 确定肠道微生物组是否处于计时能力的主动选择下。最后，一个新的实验 进化的方法将确定哪些环境压力可以选择生物钟。 这些问题的答案将有助于我们更好地理解基本原则的一般原则， 昼夜节律的组织和细胞生理的节奏调节;这种理解可以帮助我们更好地 设计出与生物钟有关的疾病的治疗方法。

Project Summary/Abstract Circadian (daily) rhythms are a crucial component of human health that regulates sleep, alertness, homeostasis, cellular signaling, 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 conditions 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 coordinate cellular organization of gene expression and information processing 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 signaling so that 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, the circadian regulation of seasonal responses and circadian interactions within communities of cells will be investigated to determine why 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 evolution approach will identify which environmental pressures can be selective for circadian clocks. The answers to these questions will help us to better understand general principles of fundamental circadian organization and rhythmic regulation of cellular physiology; this understanding can help us to better design therapies for disorders in which circadian clocks are implicated.