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）：在从蓝藻到人类的几乎所有生物体中均观察到昼夜节律。这些节奏是在“生物钟”的控制下，生物钟是一种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，激素产生和药物疗效。最近的研究表明，在大多数组织中表达的2-10%的基因表现出强大的昼夜节律振荡，这表明生物钟在我们的生理学中起着重要的作用。哺乳动物的昼夜节律是由一个自我维持的、细胞自主的转录负反馈环构成的分子振荡器（“昼夜节律钟”）调节的。周期（PER）基因是哺乳动物生物钟所必需的，PER蛋白是生物钟负反馈环的限速因子。因此，推进我们对生物钟的理解的最关键任务之一是揭示PER蛋白是如何调节的。我们建议研究两个方面的翻译后调节小鼠PER（mPER）蛋白：磷酸化和降解。我们将在两种类型的转基因小鼠中表征生物钟功能的缺陷：一种是表达转基因以破坏mPER可能激酶的功能，另一种是敲除可能靶向mPER 2进行蛋白体降解的因子。由于PER调节对生物钟机制至关重要，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，以对抗与生物钟故障相关的人类疾病，如躁狂抑郁症，慢性睡眠障碍和季节性情感障碍。