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：
7770892
负责人：
CHOOGON LEE
金额：
$ 31.06万
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 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7770892
关键词：
Affect Affinity Affinity Chromatography Antibodies Behavioral Binding Biochemical Cardiovascular system Cell Nucleus Cells Circadian Rhythms Clock protein Complement Complex Cues Cyanobacterium Defect Degradation Pathway Disease Dissection Dominant-Negative Mutation Drosophila genus Drosophila supernumerary limbs protein Electrophoresis 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 Regulation Research Personnel Role Seasonal Affective Disorder Sleep Sleep Disorders Sleep Wake Cycle Testing Time Tissue Extracts Tissues Transgenes Transgenic Mice alertness casein kinase chronic depression circadian behavioral rhythms circadian pacemaker combat drug efficacy fly human disease in vivo member mutant novel nucleocytoplasmic transport positional cloning programs protein complex 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.

从蓝细菌到人类的几乎所有生物体中都观察到了昼夜节律。这些节奏在“昼夜节律”的控制之下，这是一个遗传确定的内源性计时器，可以适应诸如白天/夜间周期之类的环境线索。我们最熟悉的昼夜节律是我们的自己的睡眠/唤醒节奏，但生理学的许多方面都有昼夜节律的节奏性激素产生和药物疗效。最近的研究表明，大多数表达的基因中有2-10％组织表现出强大的昼夜节律振荡，表明昼夜节律在我们的生理。哺乳动物的昼夜节律由分子振荡器（“昼夜节律”）调节由自我维持的细胞自主转录负反馈循环构建。（per）基因对于哺乳动物昼夜节律至关重要，而每蛋白是限制因素昼夜节律反馈循环。因此，促进我们对我们的理解的最关键任务之一时钟要揭示如何调节每个蛋白质。我们建议研究小鼠每（MPER）蛋白的翻译后调节的两个方面：磷酸化和降解。我们将以两种类型的昼夜节律功能的缺陷来表征转基因小鼠：一种表达转基因以破坏MPER可能激酶的功能，而另一个可能针对蛋白酶体降解的因素的敲除。因为每个调节对时钟机制至关重要，所以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，从睡眠到与时钟相关的人类疾病故障。我们的发现还将为开发治疗的框架提供更好的框架与时钟故障相关的战斗人类疾病，例如躁狂抑郁症，慢性睡眠障碍和季节性情感障碍。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Strong resetting of the mammalian clock by constant light followed by constant darkness.

DOI：
10.1523/jneurosci.2191-08.2008
发表时间：
2008-11-12
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Chen R;Seo DO;Bell E;von Gall C;Lee C
通讯作者：
Lee C

Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism.