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

基本信息

批准号：
7367819
负责人：
CHOOGON LEE
金额：
$ 31.45万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7367819
关键词：
Affect Affinity Affinity Chromatography Antibodies Behavioral Binding Biochemical Biochemical Genetics Cardiovascular system Cell Nucleus Cells Circadian Rhythms Clock protein Complement Complex Cues Cyanobacterium Defect Degradation Pathway Disease Disruption Dissection Dominant-Negative Mutation Drosophila genus Drosophila supernumerary limbs protein Electrophoresis Essential Genes Exhibits Feedback Genes Genetic Homologous Gene Hormones Human Human Biology Knock-out Knockout Mice Liver Extract Mammals Manic Mass Spectrum Analysis Mediating Methods Modeling Molecular Mus Organism Pathway interactions Periodicity Phosphorylation Phosphotransferases Physiology Play Post-Translational Regulation Process Production Proteins Proteolysis Proteomics Rate Regulation Role Seasonal Affective Disorder Sleep Sleep Disorders Sleep Wake Cycle Testing Thinking Time Tissue Extracts Tissues Transgenes Transgenic Mice alertness casein kinase chronic depression circadian behavioral rhythms circadian pacemaker day drug efficacy fly human disease in vivo member mutant novel nucleocytoplasmic transport positional cloning research study therapy development tool

项目摘要

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.

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，这是一种由基因决定的内源性计时器，可以适应环境线索，例如昼夜循环。我们最熟悉的昼夜节律是我们的自己的睡眠/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、激素的产生和药物功效。最近的研究表明，2-10% 的基因在大多数细胞中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命活动中发挥着重要作用生理。哺乳动物的昼夜节律由分子振荡器（“昼夜节律钟”）调节由自我维持的、细胞自主的转录负反馈环构成。期间（每）基因对于哺乳动物生物钟至关重要，而 PER 蛋白是生物钟的限速因素昼夜节律负反馈循环。因此，最重要的任务之一是增进我们对 Clock 的目的是揭示 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。我们将生物钟功能的缺陷描述为两种类型转基因小鼠：表达转基因以破坏可能的 mPER 激酶功能的小鼠，以及另一个是敲除可能针对 mPER2 进行蛋白酶体降解的因子。由于 PER 调节对于时钟机制至关重要，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，从睡眠到与生物钟相关的人类疾病故障。我们的发现还将为治疗方法的开发提供更好的框架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。