CASEIN KINASE I AND THE REGULATION OF CIRCADIAN RHYTHM

酪蛋白激酶 I 与昼夜节律的调节

• 批准号: 6835143
• 负责人: DAVID M VIRSHUP
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6835143
• 关键词: Xenopus oocyte; casein kinase; circadian rhythms; enzyme activity; fluorescence microscopy; gene expression; gene mutation; gene targeting; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; molecular cloning; nuclear transfer; phosphorylation; protein binding; protein degradation; protein structure function; protein transport; regulatory gene; suprachiasmatic nucleus; transcription factor; transfection

Circadian physiology is regulated by a cell-autonomous transcriptional negative feedback loop that influences multiple aspects of behavior. Disturbances in circadian rhythm underlie problems such as industrial and automobile accidents and sleep disorders. A detailed understanding of the function of the clock may aid in the mitigation of these problems. The genes and proteins that make up the machinery of the mammalian circadian rhythms are being identified through genetic approaches. The molecular mechanisms that underlie the intrinsic 24-hour clock can now be analyzed through the study of these regulatory elements in vivo and in vitro. Mutations in casein kinase I epsilon (CKIepsilon) both in flies and hamsters have recently been found to significantly dysregulate clock function, demonstrating that protein phosphorylation by a specific protein kinase plays a critical in the regulation of the clock. Initial mechanistic studies have suggested that CKIepsilon binds to the PERIOD proteins and through phosphorylation regulates their stability and nucleocytoplasmic trafficking. This project will examine specific mechanisms by which phosphorylation regulates the function of the circadian clock by a combination of molecular and genetic approaches.

昼夜节律生理学受细胞自主转录负反馈环调节，该负反馈环影响行为的多个方面。昼夜节律紊乱是工业和汽车事故以及睡眠障碍等问题的基础。详细了解时钟的功能可能有助于缓解这些问题。基因和蛋白质组成的哺乳动物昼夜节律的机制正在确定通过遗传方法。现在可以通过在体内和体外研究这些调控元件来分析内在24小时生物钟的分子机制。最近发现果蝇和仓鼠中的酪蛋白激酶I β（CKI β）突变显著失调时钟功能，表明特定蛋白激酶的蛋白磷酸化在时钟调节中起关键作用。最初的机制研究表明，CKI3与PERIOD蛋白结合，并通过磷酸化调节其稳定性和核质运输。该项目将通过分子和遗传方法的结合来研究磷酸化调节生物钟功能的具体机制。