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

酪蛋白激酶 le/d 和 b-Trcp 在哺乳动物生物钟中的作用

• 批准号: 7147783
• 负责人: CHOOGON LEE
• 金额: $ 32.44万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-18 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147783
• 关键词: casein kinase; circadian rhythms; genetically modified animals; human; laboratory mouse; phosphorylation; physiology; proteins; role

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.

描述（由申请人提供）：从蓝细菌到人类，几乎所有生物体都观察到昼夜节律。这些节律受到“生物钟”的控制，“生物钟”是一种由基因决定的内源性计时器，可以根据昼夜周期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，但生理学的许多方面都存在昼夜节律，包括警觉性、激素产生和药物功效。最近的研究表明，大多数组织中表达的基因中有 2-10% 表现出强烈的昼夜节律振荡，这表明生物钟在我们的生理学中发挥着重要作用。哺乳动物的昼夜节律由分子振荡器（“昼夜节律钟”）调节，该分子振荡器由自我维持、细胞自主的转录负反馈环构成。周期 (Per) 基因对于哺乳动物生物钟至关重要，而 PER 蛋白是昼夜节律负反馈循环的速率限制因素。因此，增进我们对生物钟的理解的最关键任务之一是揭示 PER 蛋白的调控方式。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。我们将描述两种转基因小鼠的生物钟功能缺陷：一种表达转基因以破坏可能的 mPER 激酶的功能，另一种敲除可能针对 mPER2 进行蛋白酶体降解的因子。由于 PER 调节对于生物钟机制至关重要，因此我们的研究结果将加深我们对昼夜节律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。我们的发现还将为开发治疗方法提供更好的框架，以对抗与时钟故障相关的人类疾病，例如躁狂抑郁症、慢性睡眠障碍和季节性情感障碍。