基于HIF-1α/EZH2/SF-1表观遗传修饰研究罗氏内异方治疗子宫内膜异位症的作用机制

子宫内膜异位症（EMs）是一种雌激素依赖的炎症性疾病，但目前抗雌激素治疗效果不佳。异位内膜局部类固醇生成因子（SF-1）低甲基化是导致局部雌激素生成的关键，且SF-1低甲基化与HIF-1α驱动的表观遗传修饰异常相关。研究发现，罗氏内异方（LSNYF）可通过抑制SF-1/P450arom通路减少雌激素生成，调控HIF-1α和EZH2改善局部缺氧状态治疗EMs，而组织局部缺氧、表观修饰改变也是EMs发病的重要机制。故本项目拟通过EMs病证结合大鼠模型和体外分离培养上皮及间质细胞等，联合氯化钴模拟缺氧环境、靶向操纵基因表达、巢式降落式甲基化PCR等技术，探讨LSNYF通过调节HIF-1α驱动的EZH2组蛋白甲基化修饰抑制SF-1介导的雌激素合成治疗EMs的作用机制，并进一步明确缺氧及EZH2表观遗传修饰与EMs发病的相关性，为LSNYF的优化应用及调控表观遗传修饰治疗EMs药物的研发提供靶点。

Endometriosis (EMs) is an estrogen-dependent inflammatory disease, but currently anti-estrogen therapy is unsatisfactory and easy to relapse. Hypomethylation of steroidogenic factor 1(SF-1) related to the epigenetic modification mediated by HIF-1α in ectopic endometrium is regarded as the key to the estrogen formation. On our preliminary study, it was found that LSNYF can reduce estrogen production by inhibiting SF-1/P450arom pathway, regulate and controll HIF-1α and EZH2 gene to improve oxygen-deficiency thus treating EMs. Moreover, the local hypoxia and epigenetic modification also take important role in the mechanisms of EMs. According to the above information, this project intends to explore the mechanism of LSNYF in treating EMs by regulating EZH2 histone methylation drived by HIF-1α gene to inhibit estrogen formation mediated by SF-1 gene, and clarify correlation between hypoxia, epigenetic modification of EZH2 and EMs. In this study, cobalt oxide would be used to imitate hypoxia environment, the models adopt the EMs rat model combined syndrome with disease and isolated epithelial, mesenchymal cells cultured in vitro, however, manipulation of gene expression and the nested PCR techniques are applied. Through this research, ultimately, the finding might further optimize the application of LSNYF and offer targets for new drugs for the treatment of EMs.