Casein Kinase I and the Regulation of Circadian Rhythm

描述（由申请人提供）：本提案研究蛋白质磷酸化如何调节哺乳动物细胞内的昼夜节律钟周期。昼夜节律是一个大约24小时的周期，调节关键的生物过程。每天的觉醒、压力激素、脂质代谢、免疫功能和细胞分裂周期的波动都是由我们身体中的分子钟控制的。生物钟调节成分的突变可以缩短或延长节律的时间，并产生重大的生理后果。生物钟是由转录、翻译和转录抑制的负反馈回路形成的。时钟定时的精确性由蛋白激酶和磷酸酶控制。酪蛋白激酶I β是一种蛋白激酶，其通过蛋白质PER 1和PER 2的周期性磷酸化来调节生物钟，控制其稳定性和定位。在这个建议中，磷酸化在调节PER功能的时钟中的作用进行了详细探讨。定量建模已被证明是非常有用的，在磷酸化的变化如何改变时钟的行为作出重要的预测。我们将使用这些研究的数据来完善我们的定量模型，并做出额外的可测试的预测。详细了解可逆的蛋白质磷酸化如何调节昼夜节律，以及详细的定量模型，可以对生物钟以及我们如何操纵它做出清晰，可测试和准确的预测，这对人类健康有重要的好处。通过药理学方法控制节奏可以缓解时差反应、轮班工作甚至季节性情感障碍带来的压力。

DESCRIPTION (provided by applicant): 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.