Coupling between Circadian Rhythms and Metaboilsm in Cyanobacteria

描述（由申请人提供）：昼夜节律是由内部生物钟产生的近24小时周期的日常行为振荡。在许多生物体中，当生物钟与外部环境中的日常周期不同步时，健康和健身就会受损。 然而，这些卫生费用背后的机制尚不清楚。我们正在追求的假设是，生物钟的一个关键功能是在预期环境变化的情况下优化新陈代谢。我们将生物物理和生物化学测量与实验驱动的数学建模相结合，在细菌模式生物细长聚球藻中研究生物钟，新陈代谢和生物体适应性之间的连锁关系。在这种生物体中，生物钟和新陈代谢之间的关系非常直接，核心昼夜节律振荡器可以在试管中使用纯化的蛋白质重建，使其成为研究这一假设的特殊动力系统。在目标1中，我们将使用纯化的蛋白质确定在体外代谢信号存在下维持稳健节律的分子机制。在目标2中，我们将确定生物钟突变体在体内的代谢效应 以及它们在将时钟输出耦合到输入的代谢反馈回路中的作用。在目标3中，我们将确定生物钟和新陈代谢之间的失调对单细胞繁殖率和能力的影响，以便将这些发现与生物体适应性联系起来。

DESCRIPTION (provided by applicant): Circadian rhythms are daily oscillations in behavior with a nearly 24-hour period that are generated by an internal biological clock. Across many organisms, health and fitness are impaired when the circadian clock does not appropriately synchronize with the daily cycles in the external environment. However, the mechanisms underlying these health costs are not clear. We are pursuing the hypothesis that a key function of the circadian clock is to optimize metabolism in anticipation of predicted changes in the environment. We are combining biophysical and biochemical measurements with experimentally-driven mathematically modeling in the bacterial model organism Synechococcus elongatus to study the interlocking relationships between clocks, metabolism, and organismal fitness. In this organism, the relationship between the clock and metabolism is very direct, and the core circadian oscillator can be reconstituted in a test tube using purified protein, making this an exceptionally power system to study this hypothesis. In Aim 1, we will determine the molecular mechanisms that maintain robust rhythms in the presence of metabolic signals in vitro using purified proteins. In Aim 2, we will determine the metabolic effects of clock mutants in vivo and their role in a metabolic feedback loop coupling clock output to input. In Aim 3, we will determine the impact of misalignment between the clock and metabolism on the reproductive rate and capacity of single cells in order to link these findings to organismal fitness.