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Molecular, cellular and physiological mechanisms of the mammalian circadian clock

哺乳动物生物钟的分子、细胞和生理机制

基本信息

批准号：
8328020
负责人：
JOHN B HOGENESCH
金额：
$ 62.22万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328020
关键词：
Address Adipocytes Advanced Sleep Phase Syndrome Animal Model Animal Testing Behavior Behavioral Behavioral Assay Biochemical Bioinformatics Biological Clocks Biological Neural Networks Biology Cell model Cells Chromosome Mapping Circadian Rhythms Data Data Analyses Data Set Defect Delayed Sleep Phase Syndrome Disease Fibroblasts Generations Genes Genetic Genomics Goals Gold Grant Hepatocyte Human Image Informatics Knockout Mice Laboratories Lead Learning Life Literature Machine Learning Mammalian Cell Memory Methods Modeling Molecular Mus Mutagenesis Mutation Neurologic Neurosciences Research Orthologous Gene Pattern Performance Periodicity Phenotype Physiological Physiology Play Probability Proteomics Psyche structure Quantitative Genetics RNA Interference Research Role Screening procedure Sleep Sleep Disorders Sleep Wake Cycle Slice System Testing Therapeutic Intervention Time Tissues Work behavior test circadian pacemaker data integration evidence base fly gene discovery gene function improved knockout animal luminescence mouse model mutant neurogenetics new therapeutic target novel novel strategies positional cloning sleep onset therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The circadian clock regulates physiology and behavior and impinges on many aspects of our daily life. Nowhere is this more obvious than control of the sleep wake cycle, where clock genes have been shown to play a role in both the timing of sleep and its quality. For example, mutations in PER2 cause familial advanced sleep phase syndrome (FASPS), while mutations in CSNK1E and CSNK1D cause FASPS and delayed sleep phase syndrome (DSPS), respectively. However, while we have learned much about the clock and how it regulates sleep, the picture is incomplete. Behavioral studies in mice and studies in human cells show that dozens to hundreds of loci impact circadian clock function. However, only a dozen genes have been investigated for their roles in regulating behavior. Testing dozens to hundreds of mice isn't practical, so a new approach is needed. Here we seek to address this gap with a novel strategy that uses, i) integrative bioinformatics to prioritize putative core clock factors, ii) new experimental methods to determine whether they interact with known clock genes and regulate clock function in several cellular or tissue slice models, and, finally, iii) for a subset of promising candidates, generate mouse models and test them for their roles in regulating circadian behavior and sleep. Completion of this research will improve our understanding of circadian rhythms and sleep and may point the way to new therapeutic targets for related disorders in humans. PUBLIC HEALTH RELEVANCE: Our internal biological clocks control many important aspects of our physiology and behavior such as the sleep-wake cycle. Genetics and large-scale genomic studies have implicated the role of a dozen canonical and hundreds of additional new genes in the circadian clock. However, almost none of the new genes have been studied in animal models for their ability to regulate sleep onset or quality. We will address this gap using bioinformatics, experimental biology, and finally through behavioral analysis. Completion of this research will improve our understanding of circadian rhythms and sleep and may point the way to new therapeutic targets for related disorders in humans.

描述（由申请人提供）：生物钟调节生理和行为，影响我们日常生活的许多方面。没有什么比控制睡眠/觉醒周期更明显的了，生物钟基因已经被证明在睡眠的时间和质量上都起着作用。例如，PER 2的突变导致家族性睡眠期提前综合征（FASPS），而CSNK 1 E和CSNK 1D的突变分别导致FASPS和睡眠期延迟综合征（DSPS）。然而，尽管我们已经了解了很多关于生物钟及其如何调节睡眠的知识，但这幅图景并不完整。对小鼠的行为研究和对人类细胞的研究表明，数十至数百个基因座影响生物钟功能。然而，只有十几个基因被研究了它们在调节行为中的作用。测试几十到几百只老鼠是不切实际的，所以需要一种新的方法。在这里，我们试图用一种新的策略来解决这一差距，该策略使用，i）综合生物信息学来优先考虑假定的核心时钟因子，ii）新的实验方法来确定它们是否与已知的时钟基因相互作用并在几种细胞或组织切片模型中调节时钟功能，最后，iii）对于有希望的候选者的子集，制作小鼠模型，并测试它们在调节昼夜行为和睡眠方面的作用。这项研究的完成将提高我们对昼夜节律和睡眠的理解，并可能为人类相关疾病的新治疗靶点指明方向。我们的内部生物钟控制着我们生理和行为的许多重要方面，如睡眠-觉醒周期。遗传学和大规模的基因组研究表明，生物钟中有十几个典型基因和数百个新基因。然而，几乎没有一个新基因在动物模型中研究过它们调节睡眠开始或质量的能力。我们将使用生物信息学，实验生物学，并最终通过行为分析来解决这一差距。这项研究的完成将提高我们对昼夜节律和睡眠的理解，并可能为人类相关疾病的新治疗靶点指明方向。