Molecular, cellular and physiological mechanisms of the mammalian circadian clock

描述（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时间和睡眠质量方面都发挥着作用。例如，PER2突变导致家族性睡眠阶段提前综合征（FASPS），而CSNK1E和CSNK1D突变分别导致FASPS和延迟睡眠阶段综合征（DSPS）。然而，虽然我们已经了解了很多关于生物钟以及它如何调节睡眠的知识，但这幅图景并不完整。对小鼠和人类细胞的行为研究表明，数十到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现实的，所以需要一种新的方法。在这里，我们试图通过一种新的策略来解决这一差距，该策略使用，i)整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)对于一个有希望的候选子集，生成小鼠模型并测试它们在调节昼夜节律行为和睡眠中的作用。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道路。

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.