生物钟基因DEC2调控睡眠的机制

Sleep is an essential process of life, and sleep or sleep-like behavior is present in all animals that have been carefully studied, ranging from worms to human. Sleep loss impairs cognitive function and is associated with increased risks of various diseases. In contrast to the importance of sleep, the mechanism (molecular mechanism in particular) regarding how it is regulated remains largely unclear. We have previously identified a mutation in the circadian clock gene DEC2 (DEC2-P384R) that is associated with a human short sleep phenotype. Moreover, transgenic mice and flies carrying this DEC2 mutation exhibit less sleep compared to wild-type animals, similar to the human subjects. This indicates that DEC2-P384R is a causative mutation leading to the short sleep phenotype observed in human subjects. In transgenic flies, this mutation also reduces the levels of a gene involved in neurotransmitter signaling that regulates sleep. Here we propose to perform detailed characterization of sleep in these fly models and assay signaling pathways known to regulate sleep to see how they are affected by the DEC2-P384R mutation. We will also conduct a screen to identify novel signaling components that genetically interact with DEC2-P384R to modulate sleep. Our study will help elucidate the molecular mechanism of sleep regulation in human, which shall contribute to improvement of human health and performance.

睡眠是一项基本的生命过程。所有仔细研究过的动物，从蠕虫到人类，都具有睡眠或类似睡眠的行为。缺乏睡眠会损害认知功能并增加罹患多种疾病的风险。尽管睡眠极为重要，睡眠的调控机制（尤其是分子机制）知之不多。申请者致力于睡眠调控机制的研究，本人所在实验室的前期研究发现生物钟基因DEC2的一个突变（DEC2-P384R)与人类少眠表型相关。携带此DEC2突变体的转基因小鼠和果蝇与野生型相比睡眠较少，与携带此突变的人表现相似，表明DEC2-P384R突变导致人的睡眠减少。在转基因果蝇里，此突变降低调控睡眠的神经递质系统基因的表达。本项目拟以转基因果蝇为模式，详细分析其睡眠，检测已知调控睡眠的信号通路是否受到DEC2-P384R突变的影响，同时进行遗传筛选找出与DEC2-P384R互作的基因并鉴定其对睡眠的影响。希望本项目的研究结果有助于阐明人类睡眠调控的分子机制，为提高人类健康水平和生活质量作出贡献。

睡眠是一项基本的生命过程，缺乏睡眠会损害认知功能并增加罹患多种疾病的风险，严重缺乏睡眠会致命。尽管睡眠极为重要，睡眠的调控机制尚不清楚，因此本项目主要针对睡眠的调控机制开展研究。由于睡眠受到生物钟与近日节律的调节，因此本项目也探讨了生物钟的调控机理与功能。主要研究成果包括以下三部分：1）探讨DEC2突变影响睡眠的机理；我们前期结果发现DEC2-P384R与人的少眠表型相关，我们在果蝇的不同脑区表达人的hDEC2-P384R，发现在近日节律神经元内表达可导致睡眠显著减少。2）构建了节律基因数据库Circadian Gene Database，包含在多个物种中mRNA呈节律性表达的基因及相关信息，并通过分析发现在不同物种中节律基因皆富集于代谢相关通路。3）揭示生物钟的新调控机制；我们发现干扰果蝇组蛋白乙酰转移酶辅因子Nipped-A导致果蝇活动节律显著延长，分子层面的研究阐明NIPPED-A通过促进组蛋白H2B的去泛素化增强生物钟基因timeless和Par-domain protein 1ε的转录，从而调控活动节律的周期。本项目计划发表论文2-4篇，实际发表标注资助的论文4篇，皆为第一作者或通讯作者论文，并培养博士1名、硕士2名。