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

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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.