Microbial regulation of vertebrate circadian clocks

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Project Summary/Abstract Within each cell, a robust molecular clock is established by transcription-translation feedback loops driven by the transcriptional activation complex CLOCK:BMAL1 and the repressors PER (period) and CRY (cryptochrome) that turn CLOCK:BMAL1 “off”. The molecular clock controls daily oscillations in the expression of over 40% of the genome to synchronize host physiology with the external environment. These oscillations are self-sustaining on the cellular level: circadian rhythms persist with similar timing even when all external cues are removed, but will align with external cues when present, a feature called entrainment. In mammals, induction of the circadian repressor PER is a universal first step in the entrainment. Microbes are ubiquitous in our environment and undergo daily fluctuations correlated with the 24-hour solar cycle, but it is not known how microbial exposure impacts circadian rhythms. This research will explore how microbial concentration affects cellular signaling cascades responsible for entrainment and will define novel innate regulators of the clock. In addition, these studies will leverage the genetic and experimental tractability of zebrafish to perform high throughput, real time kinetics of circadian responses in vivo. The ability to do whole body, non-invasive imaging in zebrafish has significant advantages over established murine models and is particularly advantageous for migratory populations such as immune cells. Furthermore, as a non-mammalian, cold-blooded vertebrate, the study of clocks in zebrafish also represents an incredible opportunity to bridge the evolutionary gap between the most well characterized animal systems: Drosophila (invertebrate) and mice (vertebrate, mammal). Together, this research will advance our fundamental understanding of vertebrate circadian clocks and how it integrates information about microbial stimulation to entrain cellular clocks at the molecular level.