This proposal studies how protein phosphorylation regulates the period of the circadian clock within mammalian cells. Circadian rhythms are a circa-24 hour cycle that regulates key biological processes. Daily fluctuations of wakefulness, stress hormones, lipid metabolism, immune function and the cell division cycle are controlled by the molecular clocks that function throughout our bodies. Mutations in regulatory components of the clock can shorten or lengthen the timing of the rhythms and have significant physiological consequences. The clock is formed by a negative feedback loop of transcription, translation, and inhibition of transcription. The precision of clock timing is controlled by protein kinases and phosphatases. Casein kinase I epsilon is a protein kinase that regulates the circadian clock by periodic phosphorylation of the proteins PER1 and PER2, controlling their stability and localization. In this proposal, the role of phosphorylation in regulating PER function in the clock is explored in detail. Quantitative modeling has proven very useful in making important predictions about how changes in phosphorylation alter the clock's behavior. We will use data from these studies to refine our quantitative model and make additional testable predictions. A detailed understanding of how reversible protein phosphorylation regulates circadian rhythms and a detailed quantitative model that makes clear, testable and accurate predictions about the clock and how we may manipulate it, can have important benefits for human health. Pharmacological manipulation of rhythms could mitigate stress from jet lag, shift work, and perhaps even seasonal affective disorder. ? ? ?
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