基于胆固醇代谢重编程探索NR5A1在子宫内膜基质细胞蜕膜化中的作用及机制

原因不明复发性流产（URSA）是尚未解决的生育难题。子宫内膜蜕膜化异常是导致孕早期URSA的主要原因之一。在子宫内膜基质细胞（ESCs）蜕膜化的进程中，胆固醇代谢可能重编程，以维持细胞胆固醇稳态。课题组的前期研究发现，NR5A1低表达与分泌中期hESCs（human ESCs）胆固醇水平降低及URSA的发生可能相关；NR5A1在小鼠着床点ESCs的表达显著高于着床旁；人工诱导蜕膜化显著上调NR5A1在小鼠子宫内膜和hESCs的表达；敲低NR5A1导致人工诱导蜕膜化的hESCs胆固醇水平显著降低和蜕膜化障碍，而补充胆固醇产生挽救效应。申请人拟利用URSA临床样本、体外细胞模型和经典小鼠模型，应用同位素标记代谢组学、转录组学等技术，描绘ESCs在蜕膜化进程中的特征性胆固醇代谢谱，阐明NR5A1重编程ESCs的胆固醇代谢，调控细胞胆固醇稳态，从而在ESCs蜕膜化中发挥关键作用的分子机制。

Unexplained recurrent spontaneous abortion (URSA) is remaining an unresolved infertility issue. One of the main causes of URSA is the dysregulated decidualization in early pregnancy. Cholesterol metabolism is reprogrammed to maintain the cholesterol homeostasis in endometrial stromal cells (ESCs) during decidualization. Our previous studies found the following results: the decreased expression of NR5A1 was associated with the cholesterol reduction in human ESCs (hESCs) during mid-secretory phase as well as the involvement of URSA; the expression of NR5A1 in mouse ESCs at the implantation site was significantly higher than that at the inter-implantation site during peri-implantation period; the expression of NR5A1 in uterine endometrium of mice and hESCs was significantly upregulated by artificially induced decidualization (AID); NR5A1 knock-down led to a significant cholesterol reduction and decidualization dysfunction in hESCs treated with AID, while cholesterol supplement rescued the decidualization. Therefore, the applicant aims to characterize the cholesterol metabolite profiles and cholesterol homeostatic regulation in ESCs during decidualization using clinical samples from URSA patients, cell models, animal study, isotope labeling metabolomics enrichment, transcriptomics, and other experimental methods, in order to clarify the molecular mechanism underlying the role of NR5A1 in reprogramming of cholesterol metabolism.