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方方面面。这一点比控制睡眠清醒周期更明显，在睡眠周期中，时钟基因已被证明对睡眠时间和睡眠质量都起到了作用。例如，PER2的突变会导致家族性睡眠相综合症(FASPS)，而CSNK1E和CSNK1D的突变会分别导致FASPS和睡眠相延迟综合征(DSSPS)。然而，尽管我们已经了解了很多关于时钟和它如何调节睡眠的知识，但这幅图还不完整。对小鼠的行为研究和对人类细胞的研究表明，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过它们在调节行为中的作用。测试几十到数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)综合生物信息学来优先考虑假定的核心时钟因素，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个细胞或组织切片模型中调节时钟功能，以及最后，iii)对于有希望的候选者的子集，生成小鼠模型并测试它们在调节昼夜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方向。

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.