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

从蓝藻到人类，几乎所有的生物都观察到了昼夜节律。这些 节律受“生物钟”的控制，这是一种由基因决定的、内源性的计时器， 能够适应环境提示，如昼夜循环。我们最熟悉的昼夜节律是我们的 有自己的睡眠/清醒节律，但在生理的许多方面都有昼夜节律，包括警觉性， 激素的产生和药物的疗效。最近的研究表明，2-10%的基因在大多数情况下都有表达 组织表现出强大的昼夜节律振荡，这表明生物钟在我们的 生理学。哺乳动物的昼夜节律是由分子振荡器(“昼夜钟”)调节的。 由一个自我维持的、细胞自主的转录负反馈环构建。期间(每次) 基因对于哺乳动物的生物钟是必不可少的，而PER蛋白是 昼夜节律负反馈环。因此，推进我们对 时钟是为了揭示PER蛋白是如何被调控的。 我们建议从两个方面研究小鼠PER(Mper)蛋白的翻译后调控： 磷酸化和降解。我们将在以下两种类型中描述生物钟功能的缺陷 转基因小鼠：一种表达转基因以破坏mper可能的激酶功能的小鼠，以及 另一个是针对蛋白酶体降解的mPER2的一个因子的敲除。 由于PER调节是时钟机制的基础，我们的研究结果将会深化 我们对昼夜节律生理学的方方面面的了解，从睡眠到与时钟相关的人类疾病 故障。我们的发现还将为开发治疗方法提供更好的框架 对抗与时钟故障相关的人类疾病，如躁郁症、慢性睡眠 精神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.