磷脂酰乙醇胺通过间质上皮转化（MET）调控体细胞重编程的机制研究

Metabolic remodeling has emerged as key regulators of somatic cell reprogramming. Due to the complexity of lipid metabolism, rules and roles of lipid remodeling remain unclear. Specific lipid molecules and pathways involved in reprogramming need further investigation. Our previous work found key regulator of lipid metabolism, Srebp1, regulates reprogramming (Stem Cells, 2016). Using lipidomics approach, we revealed phospholipid remodeling occurred during reprogramming and identified phosphatidylethanolamine (PE) as key lipid in the early stage of reprogramming. PE regulated mesenchymal-epithelial transition (MET) during reprogramming. Preliminary mechanistic studies revealed PE binding protein Pebp1 modulated MET and most genes PE-regulated during reprogramming. The functional similarity between PE and Pebp1 promoted us to hypothesize PE coordinate Pebp1 to regulate MET in reprogramming. In this project, we aim to explore specific lipids and pathways involved in lipid remodeling during reprogramming, and to reveal mechanisms by which PE coordinate Pebp1 to control MET and reprogramming. This project will elucidate phospholipid remodeling during reprogramming and provide insights into metabolic regulation of cell fate.

近年来代谢重塑被发现在细胞命运决定中起重要作用。由于脂代谢的复杂性，其在细胞命运决定中的重塑规律及作用仍不清楚，关键的脂类分子及代谢途径仍需更深层次的研究。我们的工作发现脂代谢因子Srebp1调控高效安全的重编程（Stem Cells, 2016），后续我们利用脂质组学发现了体细胞重编程中的磷脂重塑现象，鉴定出磷脂酰乙醇胺（PE）为重编程早期关键的脂类，调控重编程中的间质上皮转化（MET）。初步机制探索发现PE结合蛋白Pebp1与PE在重编程中调控相似的下游，且与MET相关，由此我们推测PE与Pebp1协同调控重编程中的MET。本项目拟在此基础上，进一步深入研究体细胞重编程中的磷脂重塑规律及代谢途径，研究磷脂PE与Pebp1在重编程中的关系及其调控MET的分子机制。本研究将有望阐明重编程早期的磷脂重塑规律，揭示其代谢调控途径及其对MET的调控机制，为探索细胞命运转变的代谢调控提供重要思路。

脂代谢重塑是细胞命运转变中的关键步骤，而磷脂作为脂代谢中的一大种类在细胞命运调控中起着重要作用。本项目以体细胞重编程，胚胎干细胞分化等为模型，研究脂代谢重塑规律并鉴定关键磷脂分子。研究发现多能性退出的过程伴随着中性脂水解速率的上升，其上升是由分子伴侣介导的自噬调控，并发现加速中性脂水解可促进多能性退出。进一步机制研究利用脂质组学，发现中性脂水解影响磷脂稳态，并鉴定出磷脂酰乙醇胺与心磷脂为多能干细胞命运调控的关键磷脂分子，发现磷脂重塑可调控表观遗传及多能干细胞命运。本工作不仅揭示了脂代谢稳态在多能性维持中的作用及其调控蛋白，鉴定出磷脂酰乙醇胺和心磷脂为关键磷脂，还发现了脂代谢调控表观遗传及细胞命运的新模式。由于脂代谢变化及线粒体重塑存在于许多生理病理过程中，包括胚胎停滞，肿瘤发生，脂肪肝及神经退化等，这一工作为探索这些生理病理过程的机制提供了全新的思路。

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