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

描述（由申请人提供）：从蓝藻到人类，几乎所有生物都有昼夜节律。这些节律是由“生物钟”控制的，这是一种由基因决定的内源性计时器，可以根据昼夜循环等环境线索进行调整。我们最熟悉的昼夜节律是我们自己的睡眠/觉醒节律，但昼夜节律在生理的许多方面都存在，包括警觉性、激素产生和药物功效。最近的研究表明，在大多数组织中表达的2-10%的基因表现出强烈的昼夜节律振荡，这表明生物钟在我们的生理中起着重要作用。哺乳动物的昼夜节律是由一个分子振荡器（“生物钟”）调节的，这个分子振荡器是由一个自我维持的、细胞自主的转录负反馈回路构成的。周期（Per）基因对哺乳动物生物钟至关重要，而Per蛋白是昼夜节律负反馈回路的限速因子。因此，推进我们对生物钟的理解的最重要的任务之一是揭示PER蛋白是如何被调节的。我们建议研究小鼠PER （mPER）蛋白翻译后调控的两个方面：磷酸化和降解。我们将在两种类型的转基因小鼠中表征昼夜节律钟功能的缺陷：一种表达转基因以破坏mPER可能激酶的功能，另一种表达敲除可能靶向mPER2的蛋白体降解因子。由于PER调节是生物钟机制的基础，我们的研究结果将加深我们对昼夜生理学各个方面的理解，从睡眠到与生物钟故障相关的人类疾病。我们的发现也将提供一个更好的框架，用于治疗与生物钟失调相关的人类疾病，如躁狂抑郁症、慢性睡眠障碍和季节性情感障碍。

DESCRIPTION (provided by applicant): 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 proteosomal 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.