Regulation and Significance of Sustained Circadian Oscillations

项目摘要/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、 动态平衡、细胞信号和许多其他生物过程。这种现象的魅力在于 解释生化机制(I)如何强健地维持长周期(~24小时)的振荡 频率使时间保持如此精确，并且(Ii)增强了在自然环境中的健康。这些问题仍然存在 昼夜节律领域中的关键未解问题。例如，自适应值不是 对于最明显的昼夜节律特征--恒定条件下强劲的自我维持振荡来说，这是显而易见的。如果 对未来时间事件(如黎明、黄昏等)的“预期”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式“沙漏计时器”还不够吗？然而，进化 无处不在地选择一种在非自然连续条件下保持自身的振荡器作为计时器 调节日常过程，这一特征形成了昼夜节律的核心定义属性。这个 这个项目的总体目标是确定哪些节奏环境的特征提供了选择性 协调细胞组织基因表达和信息处理的压力，以促进 昼夜节律计时的特性。识别可能导致以下结果的选择性压力和进化步骤 生物计时将使我们能够更深刻地理解昼夜节律的机制和信号 他们可能会得到加强，以帮助人类的健康和表现。 我们将利用模型系统的独特特性，通过一个 多方面的方法。首先，在自由生活的生物体中，季节性反应的昼夜调节和 将调查细胞群落内的昼夜节律相互作用，以确定为什么持续的振荡器 必然是适应性的。第二，宿主/微生物群关系的时间维度将被操纵以 确定肠道微生物群是否处于主动选择的计时能力之下。最后，一个新颖的实验 进化方法将确定哪些环境压力对昼夜节律时钟具有选择性。 这些问题的答案将有助于我们更好地理解基本原理 细胞生理学的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。

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.