三棱-莪术通过调控FABP4表达干预子宫内膜异位症的配伍机制研究

Endometriosis (EMS) is a common disease in women and roughly 10% of women are affected globally. It may cause dysmenorrhea, irregular menstruation, dyspareunia and dysgenesis, etc. Increasing evidence suggests adipocyte-type fatty acid binding protein (FABP4), a small protein that promotes cell migration and angiogenesis, is up-regulated during EMS in the uterus. Whether FABP4 plays a causal role in the pathogenesis of EMS, however, is still elusive. The mixture of Rhizoma sparganii and Rhizoma Curcumae has been effective against EMS clinically in ancient China with the underlying mechanism being lacking. In this project, by using a EMS mouse model, we are going to test the hypothesis that Rhizoma sparganii-Rhizoma Curcumae alleviates EMS through a mechanism involving FABP4. By completing this project, we are going to establish a better understanding of the roles of FABP4 in the pathogenesis of EMS and the role of hizoma sparganii and Rhizoma Curcumae in treating EMS, which may facilitate the development of novel therapeutic strategies for EMS.

子宫内膜异位症(EMS)是妇科常见病，在育龄期妇女中发病率约10%，可致痛经、性交痛、不孕等。至今发病机制不清，且治疗困难。其疾病过程中出现的迁移、侵袭、血管形成与恶性肿瘤类似。越来越多的证据表明，脂肪细胞型脂肪酸结合蛋白(FABP4)是一种能够促进细胞迁移和血管生成的小蛋白，在EMS异位病灶中表达增强，但其在EMS发病中所起的作用仍不清楚。三棱-莪术相须配伍，是临床治疗EMS的常用药对。课题组前期研究证实，两药等比配伍对实验性EMS有良好改善作用，但配伍机制尚缺乏科学研究。本项目拟建立EMS荧光小鼠和细胞模型，从整体、细胞、代谢物水平，确定FABP4在异位、在位内膜和细胞中的分布，探讨FABP4在EMS发病中所起的作用，并基于调控FABP4表达进行三棱-莪术的配伍机制研究。本项目的完成，对深入探讨EMS发病机理，揭示三棱-莪术治疗EMS的分子机制，阐释两药配伍的科学内涵都具有重要意义。

项目组收集临床子宫内膜异位症（EMS）患者病灶，并与正常人子宫内膜比较，显示脂肪酸结合蛋白4（FABP4）呈高表达；构建EMS大鼠模型，同样证实FABP4在异位病灶中呈高表达。原代培养EMS患者的异位内膜间质细胞，并构建了FABP4过表达和敲低的细胞模型，研究FABP4在EMS发病过程中的作用。结果发现，FABP4促进了异位内膜间质细胞的增殖和迁移，减少了细胞的凋亡；而使用三棱莪术治疗后能够下调FABP4的表达，促进细胞的凋亡，抑制细胞迁移，并且配伍使用优于单独使用。进而，我们复制了EMS小鼠模型，并构建了FABP4过表达和敲低的EMS小鼠模型，从整体水平验证了FABP4能够促进异位病灶的生长。经三棱莪术治疗8周后，异位病灶的体积明显减小，其作用与药物下调异位病灶组织中FABP4的表达，减轻腹腔炎症因子水平，上调凋亡基因Caspase3、Bax mRNA水平，下调Bcl2 mRNA表达，抑制侵袭蛋白和血管内皮生长因子的表达有关。并且发现，两药配伍的效果优于单独使用，说明两味药物配伍起到了协同增效的作用。本项目为研发EMS治疗用药提供了新的思路和参考。