磷脂酰胆碱在LET-607寿命决定通路中的功能与机制研究

长期以来，脂代谢尤其是脂肪酸代谢，一直是代谢研究领域的热点。然而，膜脂作为细胞内含量最丰富、结构最多样的脂类，对其调控和功能的认识尚处于起步阶段。研究发现，衰老与膜脂之间存在密切联系，多种膜脂的含量随动物衰老而变化，然而，当前对膜脂在寿命决定中的调控和功能所知甚少。代谢和寿命调控机制在进化上高度保守，利用模式动物秀丽隐杆线虫，申请者前期研究鉴定出调控膜脂代谢的新转录因子LET-607，抑制其活性可特异地下调不饱和磷脂酰胆碱的含量。更为重要的是，该类膜脂水平的降低可激活长寿转录因子DAF-16，从而延长动物寿命，将磷脂酰胆碱与寿命决定相关联。在此基础上，本项目拟利用秀丽线虫为主要模型，辅以哺乳动物细胞，综合高通量筛选、生化分析和遗传互作分析等手段，研究磷脂酰胆碱在let-607寿命决定通路中的调控、功能及机制。本研究有望为膜脂的调控和功能提供新内容，有助于从膜脂的层面理解寿命决定的代谢基础。

The regulation and function of lipid metabolism, especially fatty acid metabolism, have been extensively explored. However, the regulation and function of membrane lipids, the most abundant and complex lipid species in cells, are only beginning to emerge. Numerous studies have shown that the contents of multiple membrane lipid species correlate with age. However, little is known about the roles of membrane lipids in lifespan determination. By using C. elegans as a model organism, our preliminary data have identified LET-607 as a novel transcriptional regulator of membrane lipid metabolism and lifespan. Knockdown of let-607 specifically decreased the contents of unsaturated phosphatidylcholine, which in turn activated the longevity transcription factor DAF-16 and extended lifespan, therefore linking phosphatidylcholine to lifespan regulation. In this project, we propose to study the regulation of phosphatidylcholine by LET-607 and dissect the molecular mechanisms of how phosphatidylcholine regulates lifespan, using combined approaches of highthrouput screening, biochemical analysis of membrane lipids and genetic epistatic analysis. Further, whether the mechanisms identified above are evolutionarily conserved will also be tested in mammalian cell culture system. The completion of this project will provide novel insight into the regulation and function of membrane lipids, and help to understand the metabolic basis of lifespan determination.