子宫内膜异位症（内异症）是常见难治病，发病机制尚不明确。内源性脂类化合物脂氧素（LXA4）是新型雌激素受体调节剂。我们已报道LXA4抑制小鼠内异症的发生，内异症患者LXA4水平下降。本项目前期研究发现上皮-间质转化（EMT）参与内异症进程，LXA4既可通过自身受体ALXR抑制p38MAPK通路，也能直接与雌激素E2竞争性结合雌激素受体ERβ，调节转录因子ZEB1启动子区活性，抑制内异症EMT。本课题将系统研究LXA4抑制内异症EMT进程的分子机制。首先，从分子和细胞水平阐明LXA4结合ALXR，抑制p38MAPK和ERβ磷酸化，阻碍EMT；证实LXA4与E2竞争性结合ERβ受体，改变ZEB1表达，抑制EMT的分子机理；接着运用ERβ敲除的内异症小鼠模型和临床样品，在体内水平阐明LXA4通过拮抗E2诱导的EMT而抑制内异症的机制，为内异症发病机制的解析和治疗靶点的筛选提供参考。

Endometriosis is a common and refractory disease. The pathogenesis of the disease is unclear now. Lipoxin (LXA4), one of the endogenous lipid compounds, was a novel estrogen receptor modulator. Our published results showed that the level of LXA4 decreased in patients with endometriosis. Previous studies of this project indicated that epithelial-mesenchymal transition (EMT) was involved in the pathogenesis of endometriosis. LXA4 can not only act through its receptor ALXR-p38MAPK pathway, but also can work by directly and competitively binding to ERβ without ALXR, to modulate the expression of ZEB1, and thus inhibit the EMT in endometriosis. The inhibitory mechanism of LXA4 on EMT in endometriosis will be systematically elucidated at the molecular, cellular, mice model and clinical sample levels. Firstly, we will reveal the mechanism in vitro by which LXA4 binds to ALXR, inhibits the phosphorylation of p38MAPK and ERβ, affects the expression of ZEB1, and inhibit EMT. We will also validate that LXA4 competitively binds to ERβ with E2, modulates the expression of ZEB1, and then inhibits EMT. Secondly, the ERβ knockout mice with endometriosis and the clinical samples will be utilized to prove that LXA4 could block the EMT induced by E2 and inhibit endometriosis in vivo. Our studies will provide the reference for the understanding of the pathogenesis of endometriosis and the development of potential therapeutic target.