The Circadian Rhythms of Intestinal Stress: An analysis of Mechanism and Conservation

环境压力影响着所有的动物，为了生存，它们已经进化到能够有效地恢复。肠道是一个经常经历环境压力的组织，因为有害的病原体和化学物质经常被吃掉。从昆虫到哺乳动物，它的应激反应在进化上是保守的：相同的基因和分子途径激活肠道中的干细胞分裂和替换受损细胞。通过果蝇，我们发现肠道应激反应以24小时为周期发生，而干细胞中的生物钟引导着这一过程。生物钟是一种光敏基因系统，存在于所有生物体中，用于记录时间。利用光照水平，生物钟调节昼夜活动的行为和其他过程，其全面程度才刚刚开始得到重视。******压力信号受生物钟调节的想法是一个新颖的话题，该提案将招募5名研究生和10名本科生来研究这一领域。以果蝇为模型系统，我们将研究肠道生物钟调节的生化机制。我们已经建立了一个新的昼夜节律钟活动荧光报告器，它将被用来记录肠道不同细胞对光的反应。我们将在肠道干细胞中进行基因筛选，为未来的研究寻找新的生物钟靶点。最后，我们将研究一个与炎症有关的基因，它可能是由时钟驱动的，如何将一天中的时间与压力反应联系起来。******一个更大的问题是，压力和修复的昼夜节律控制是否在进化上是保守的，以及自然界中的动物如何适应季节性光照水平的变化。我们将与大湖环境研究所合作，探索奇努克鲑鱼的这些过程。鲑鱼的栖息地范围很广，在它们的生命周期中，当它们向北迁徙时，会经历巨大的季节性明暗变化。这使得鲑鱼成为回答这个问题的理想模型系统。******果蝇遗传学是研究发生在所有动物身上的基本机制的强大系统。我们的长期目标是应用果蝇的见解来研究实验室、细胞培养和自然界中不同动物的应激反应时间。

Environmental stress affects all animals, which have evolved to recover effectively in order to survive. The intestine is a tissue that experiences frequent environmental stress because harmful pathogens and chemicals are often eaten. Its stress response is evolutionarily conserved from insects to mammals: the same genes and molecular pathways activate stem cells in the intestine to divide and replace damaged cells. Using the fruit fly, Drosophila, we discovered that the intestinal stress response occurs with a 24h cycle, and that the circadian clock guides this process in stem cells. Circadian clocks are a system of light-sensitive genes that are present in all organisms to keep track of time. Using light levels, the circadian clock regulates day/night activity in behaviour and other processes, the full extent of which is only beginning to be appreciated. ******The idea that stress signaling is regulated by the circadian clock, is a novel topic, and this proposal will enlist 5 graduate and 10 undergraduate students to study this area. Using Drosophila as a model system, we will study the biochemical mechanisms underlying clock-regulation of the intestine. We have built a new fluorescent reporter of circadian clock activity, which will be used to record how the different cells of the intestine respond to light. We will perform a genetic screen in intestinal stem cells to find new clock targets for future study. Finally, we will investigate how a gene involved in inflammation, which may be driven by the clock, links time of day to the stress response. ******A bigger question is whether circadian control of stress and repair is evolutionarily conserved, and how animals in nature adapt to seasonal light level changes. We will explore these processes in Chinook salmon, in collaboration with the Great Lakes Institute for Environmental Research. Salmon occupy a great range of habitats, and experience tremendous seasonal light/dark changes when they migrate north during their life cycle. This makes salmon an ideal model system to answer this question. ******Drosophila genetics are a powerful system to investigate basic mechanisms which occur in all animals. Our long term goals are to apply insights from Drosophila to study the timing of the stress response in different animals in the laboratory, in cell culture, and in nature.