子宫内膜异位症腹腔微环境血红素稳态失调及其病理效应机制

周期性经血逆流是子宫内膜异位症（EMS）重要病因；也是反复考验腹腔血红素稳态调控的独特生理事件。由血红素结合蛋白（Hx）、巨噬细胞（Mφ）和子宫内膜间质细胞（ESC）中输入/输出通道、合成/分解调控因子、穿梭于各细胞器间去毒化转运血红素的分子伴侣共同构成疏浚微环境血红素的“水利枢纽”，避免了血红素毒性。基于前期研究发现EMS患者存在腹腔血红素蓄积；高血红素可抑制Mφ吞噬功能、诱发ESC低氧耐受等生物学行为改变，我们提出“腹腔微环境血红素稳态失调介导子宫内膜异位症”的假说。本项目借助Mφ/ESC三维立体共培养体系与动物模型，揭示腹腔血红素稳态失调的成因；稳态失调诱导Mφ/ESC氧化损伤、低氧应激、免疫耐受、雌孕激素反应性等介导EMS发生、发展的病理效应机制；旨在循EMS病因机制探寻非激素治疗的潜在靶点或途径，验证修复腹腔微环境血红素稳态的综合干预措施将有利于防治EMS发生、发展。

Cyclical menstrual reflux plays an important role in the pathophysiology of endometriosis (EMS). It repeatedly challenges the maintenance of heme homeostasis within the peritoneal cavity. The mechanism to maintain heme homeostasis is dependent on the coordinated action of heme scavenger hemopexin (Hx) in the peritoneal fluid and heme metabolism related proteins in macrophages (Mφ) and endometrial stromal cells (ESC), including heme transporters, heme synthesis molecules, heme catabolism molecules and heme chaperone. These factors dredged the peritoneal heme like "water conservancy hubs", maintaining the heme homeostasis and protecting cells from heme toxicity. Our previous studies have confirmed that heme accumulated abnormally in the peritoneal fluid of patients with EMS. High level of heme can not only inhibit phagocytic ability of Mφ but also induce hypoxia response and other unusual biological behaviors in ESC. Therefore, we propose the hypothesis that the disturbance of heme homeostasis in peritoneal microenvironment contributes to the development of EMS. This study intends to use a three-dimensional co-culture system of Mφ with ESC and mouse models to reveal the underlying causes of the impaired heme homeostasis, and to analyze how it affects the progression of EMS via its regulation on cell oxidative damage, hypoxic stress, immune tolerance as well as estrogen/progesterone signaling. The aim of this study is to explore the potential target of non-hormonal therapy based on the pathogenesis of EMS and to prevent the occurrence and development of EMS by comprehensive intervention of repairing heme homeostasis.