Temperature and metabolic compensation mechanisms in a circadian clock system

项目摘要/摘要 生物钟是细胞内的酶系统，提供可靠的生化 代表当地时间，对不同地区的健康产生深远影响 有机体。与大多数酶不同的是，生物钟对一系列的 生理温度和细胞能量水平，以便生物体能够预测 可靠的黎明和黄昏。生物钟的另一个标准是它们可以 通过环境线索传递，从而与当地时间保持同步。 然而，这些定义特征的机制仍未完全解决 任何有机体，因此代表着整个领域知识的显著差距 生物计时。因此，未来五年的总体愿景是建立 根据我们之前的工作，阐明了温度和代谢的机制 蓝藻生物钟的补偿和夹带，一个广泛的系统 受到生物钟团体的重视。因为蛋白质及其相互作用 不管是什么生物体，时钟机制的基础都是在这里学到的教训 作为科学界在不同领域工作的重要参考点 生物钟。在过去的20年里，我们在以下方面有了许多有影响力的发现 蓝藻生物钟的机制和开发的创新方法和 一路上的工具。我们实验室最近在体外重建了完整的蓝藻生物钟 以便可以在几天内对每个组件进行实时监控，并且我们的 精炼和预测模型是我们假设的框架 温度补偿、代谢补偿和夹带的机制。 因此，我们处于非常有利的地位，能够成功地填补这些关键的知识空白。 这里提出的工作的一个主要预期结果是详细的因果关系 将体内时钟蛋白行为和相互作用与时钟表型联系起来的模型。

Project Summary/Abstract Circadian clocks are intracellular enzymatic systems that provide a reliable biochemical representation of local time with profound consequences to health across diverse organisms. Unlike most enzymes, biological clocks are insensitive to a range of physiological temperatures and cellular energy levels so that organisms can anticipate dawn and dusk reliably. Another criterion of circadian clocks is that they can be entrained through environmental cues and thereby stay synchronized to local time. However, the mechanisms of these defining hallmarks remain incompletely resolved in any organism, and thus represent outstanding gaps in knowledge across the field of biological timekeeping. Therefore, the overall vision for the next five years is to build upon our prior work to elucidate the mechanisms of temperature and metabolic compensation and entrainment in the circadian clock of cyanobacteria, a system widely valued by the circadian clocks community. Because proteins and their interactions underpin clock mechanisms regardless of organism, lessons learned here are expected to serve as important points of reference for the scientific community working on diverse circadian clocks. Over the past 20 years, we have made many impactful discoveries on mechanism of the cyanobacterial clock and developed innovative methodologies and tools along the way. Our lab recently reconstituted the intact cyanobacterial clock in vitro such that each component can be monitored in real time over several days, and our refined and predictive model is the framework for our hypotheses regarding mechanisms of temperature compensation, metabolic compensation, and entrainment. Thus, we are very well positioned to succeed at filling these critical gaps in knowledge. A major expected outcome of the work proposed here is a detailed cause-and-effect model linking clock protein behavior and interactions to clock phenotypes in vivo.