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

• 批准号: 9349043
• 负责人: JOHN B HOGENESCH
• 金额: $ 38.68万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349043
• 关键词: Molecular; cellular; physiological; mechanisms; mammalian

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.

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。