氧化应激在子宫内膜异位症相关性不孕中的作用机制及干预研究

约达40%的子宫内膜异位症（内异症）患者合并不孕，但原因不明。氧化应激参与多种生理病理过程，是引起内异症不孕的关键因素。子宫内膜方面，我们发现过度氧化应激可能通过NF-κB调控RNA甲基化转移酶METTL3，活化的METTL3-circFoxO3反馈环路调节在位内膜细胞自噬并参与内膜蜕膜化，导致患者内膜容受性下降。卵巢卵泡方面，我们的研究提示过度氧化应激调控患者卵巢颗粒细胞内质网应激，通过诱导细胞衰老影响卵泡发育成熟；多组学联合分析提示，过度氧化应激可能通过对磷脂酰肌醇生物合成关键酶的m6A修饰，调控卵泡微环境甘油磷脂水平，从而影响患者卵泡发育成熟。本项目将系统研究氧化应激在内异症患者内膜和卵巢中作用机制，创新发现m6A修饰参与在位内膜细胞自噬及蜕膜化，首次提出卵巢颗粒细胞m6A修饰介导的甘油磷脂代谢途径调控内异症患者的卵泡发育成熟。本项目还将明确抗氧化剂在改善内异症模型小鼠生育力的机制。

About 40% of patients with endometriosis suffer from infertility, while the cause is unknown. Oxidative stress is involved in a variety of physiological and pathological processes, which is a key factor related to endometriosis infertility. In the aspect of endometrium, we found that excessive oxidative stress may regulate the RNA methyltransferase METTL3 by NF-κB signaling. And the activated METTL3-circfoxO3 feedback loop regulated autophagy of eutopic endometrial cells and involved in regulation of endometrial decidualization, which resulting in depression of endometrial receptivity. In terms of ovarian follicles, our study suggested that excessive oxidative stress regulated endoplasmic reticulum stress of ovarian granulosa cells from endometriotic patients, which aggravated cell senescence and interfered follicular development and maturation. Conjoint analysis results of multiple omics suggested that excessive oxidative stress may affect follicular development and maturation by modifying the m6A RNA methylation on key enzyme of phosphatidylinositol biosynthesis, which regulating glycerol phospholipid level of microenvironment of follicles. In this project, we will systematically study the mechanism of oxidative stress in endometrium and ovary of patients with endometriosis. RNA methylation in the processes of autophagy and decidualization in ectopic endometrial cells will be investigated. The glycerol phospholipid metabolic pathway mediated by m6A modification of ovarian granulosa cells regulating follicular development and maturation in patients with endometriosis will be studied for the first time. This project will also involve the research on the mechanism of antioxidants in improving the fertility of mice with endometriosis.