Roles of casein kinase le/d and b-Trcp in the mammalian circadian clock

从蓝藻到人类，几乎所有的生物都有昼夜节律。这些 生物节律是在"生物钟"的控制下，生物钟是一种由基因决定的内源性计时器， 可以适应环境的提示，如昼夜循环。我们最熟悉的昼夜节律是我们的 自己的睡眠/觉醒节律，但在生理学的许多方面，包括警觉性， 激素产生和药物功效。最近的研究表明，2 - 10%的基因表达在大多数 组织表现出强大的昼夜节律振荡，这表明生物钟在我们的生活中起着重要作用。 physiology.哺乳动物的昼夜节律是由一个分子振荡器（"昼夜节律钟"）调节的。 由自我维持的细胞自主转录负反馈环构建。周期（每） 基因是哺乳动物生物钟所必需的，PER蛋白是哺乳动物生物钟的限速因子。 昼夜负反馈回路因此，促进我们对人类社会的理解的最关键的任务之一， 时钟是揭示PER蛋白是如何调节的。 我们建议研究小鼠PER（mPER）蛋白的翻译后调节的两个方面： 磷酸化和降解。我们将描述两种类型的生物钟功能的缺陷， 转基因小鼠：表达转基因以破坏mPER的可能激酶的功能的小鼠，以及 另一个是可能靶向mPER 2进行蛋白酶体降解的因子的敲除。 由于PER调节对时钟机制是如此重要，我们的研究结果将进一步深化 我们对生物钟生理学的各个方面的理解，从睡眠到与生物钟相关的人类疾病， 故障我们的发现还将为治疗方法的发展提供更好的框架， 对抗与生物钟故障有关的人类疾病，如躁狂抑郁症、慢性睡眠 情感障碍和季节性情感障碍

Circadian rhythms have been observed in nearly all organisms from cyanobacteria to humans. These rhythms are under the control of the "circadian clock," a genetically determined, endogenous timekeeper that can adjust to environmental cues like the day/night cycle. The circadian rhythm most familiar to us is our own sleep/wake rhythm, but there is circadian rhythmicity in many aspects of physiology including alertness, hormone production and drug efficacy. Recent studies showed that 2-10% of genes expressed in most tissues exhibit robust circadian oscillations, suggesting that the circadian clock plays important roles in our physiology. The mammalian circadian rhythms are regulated by a molecular oscillator ("circadian clock") constructed from a self-sustaining, cell-autonomous transcriptional negative feedback loop. Period (Per) genes are essential for the mammalian circadian clock and PER proteins are rate-limiting factors for the circadian negative feedback loop. Thus, one of the most crucial tasks to advance our understanding of the clock is to uncover how PER proteins are regulated. We propose to study two aspects of posttranslational regulation of mouse PER (mPER) proteins: phosphorylation and degradation. We will characterize defects of circadian clock function in two types of genetically modified mice: one expressing a transgene to disrupt the function of likely kinases for mPER, and the other a knockout for a factor likely to target mPER2 for proteasomal degradation. Because PER regulation is so fundamental to the clock mechanism, the results of our studies will deepen our understanding of all aspects of circadian physiology, from sleep to human diseases associated with clock malfunction. Our discoveries will also provide a better framework for the development of treatments to combat human disorders associated with clock malfunction such as manic depression, chronic sleep disorder and seasonal affective disorder.