DNA甲基化介导CYP11A1调控滋养层细胞自噬诱发子痫前期的机制研究

The pathogenesis of Preeclampsia (PE) has been a hot topic in obstetrics research. Abnormalities in autophagy, DNA methylation, oxidative stress, and related gene expression in placenta have been shown to be closely related to the pathogenesis of PE，but the exact mechanism remains unclear. Our previous studies found that the expression of CYP11A1 and autophagy associated protein 7 (ATG7) was significantly increased in the placenta of PE. The binding sites of miR-296 and the mRNA of the ATG7 and CYP11A1 were predicted by TargetScan. The expression of CYP11A1 in trophoblast cells was influenced by its DNA epigenetic modification. The expression of DNMT3a was down regulated in PE derived placentas. Therefore, we propose a hypothesis, that DNMT3a expression was down-regulated in placental trophoblast cells, which reduced the DNA methylation level of CYP11A1, leading to the increase of CYP11A1 expression. While The abnormal expression of CYP11A1 can promote the expression of ATG7 by adsorbing miR-296, resulting in enhanced autophagy of trophoblast cells, which ultimately leads to the occurrence of PE. This project intends to detect relevant molecules in PE clinical specimens, determine the precise regulation mechanism of this pathway by cytological experiments, reveal the mechanism of DNA methylation mediated CYP11A1 regulation of trophoblast cell autophagy in the pathogenesis of PE.

子痫前期(Preeclampsia,PE)的发病机理是产科研究的热点问题。细胞自噬、DNA甲基化等的异常与PE发生密切相关，但具体机制仍不清楚。本课题组前期发现：PE胎盘中CYP11A1和细胞自噬相关蛋白7(ATG7)的表达明显升高；miR-296与ATG7、CYP11A1的mRNA存在结合位点；滋养细胞中CYP11A1的表达受其DNA表观修饰的影响；PE胎盘中DNMT3a的表达下调。据此我们提出：胎盘滋养细胞中DNMT3a表达下调，降低了CYP11A1的DNA甲基化水平，导致CYP11A1表达上调；而异常表达的CYP11A1通过吸附miR-296促进下游ATG7的表达，导致滋养细胞自噬功能增强，最终导致PE的发生。本项目拟对PE临床标本进行相关分子的检测，通过细胞学实验明确该通路的精确调控机制，为PE防治提供新思路。