MFG-E8在异位子宫内膜中调控细胞外基质重建和血管生成的机制研究

Endometriosis is a common gynecologic disorder in women at reproductive age, it is well accepted that the reflux of shed endometrium attaches, implants and invades on the peritoneal surface or surrounding tissue. However, its molecular mechanism remains unclear. A secreted protein, milk fat globule-epidermal growth factor 8 (MFG-E8), also called lactadherin, has been found to play an important role in tumor invasion，such as regulating tissue remodeling and angiogenesis. Interestingly, endometriosis is also the result of endometrium remodeling and angiogenesis. From our preliminary study, MFG-E8 was discovered in the endometriosis implants that suggested MFG-E8 is associated with endometriosis. Therefore, we hypothesized that dysregulation of MFG-E8 may involve in endometrium implants migration, invasion and angiogenesis, which in turn correlates with the pathogenesis of endometriosis. To test this hypothesis, we will employ an established model, in vitro 3D culture system, to mimic the endometrium. By using this system as well as immunohistochemistry, Western blot, and RNAi techniques, we aim to characterize the functional changes in extracellular matrix under the upregulating or silencing MFG-E8. Additionally, we aim to investigate the effects of MFG-E8 in endothelial cells, including proliferation, adhesion and sprouting, to reveal the regulatory role of MFG-E8 in angiogenesis contributing to endometriosis. The findings of this study will provide first evidence demonstrating endometriosis resulting from dysregulation of MFG-E8. The investigation of endometrial MFG-E8 is essential to better understand, not only the biological effects but also its potential as diagnostic biomarker for early detection of endometriosis. More importantly, this molecule could be potential therapeutic targets to improve endometriosis symptoms and treatment. The ultimate goal of this study is to provide data for an easy and quick test to measure soluble MFG-E8 in prediction of endometriosis risk, and to translate these findings into the use of this modulator to improve the life quality in patients with endometriosis.

子宫内膜异位症是辅助生殖技术中的常见疾病。内膜组织在宫腔外发生粘附侵袭、完成血管生成是内异症发生的关键步骤，其病变机理尚不清晰。研究表明，人乳脂球表皮生长因子(MFG-E8)对肿瘤组织重建和血管再生有促进作用，其病理变化与内异症形成相似。我们预实验结果提示，异位内膜中存在MFG-E8蛋白，可能参与调控内异症的发生。因此提出假说： MFG-E8蛋白的表达失调会影响异位内膜的形成，促进内异症的发生发展。我们将通过子宫内膜三维培养体系，采用RNA干扰，Western blot，免疫组化等手段，从分子、细胞、组织水平探讨MFG-E8在细胞外基质降解中的分子机制；通过血管内皮细胞研究细胞增生、粘附力和新生血管形成，探讨MFG-E8在异位内膜血管生成中的作用，进而阐明MFG-E8调控异位内膜组织重建的机理。本课题将以MFG-E8的功能这个新视点揭示异位内膜的形成机制，为内异症诊治提供新思路。

子宫内膜组织可在宫腔外发生粘附侵袭和血管生成等过程，完成异位内膜种植的关键步骤，迄今对病变机理仍知之甚少。研究表明，人乳脂球表皮生长因子(MFG-E8)可促进肿瘤组织重建和血管再生，病理变化与内异症形成相似。本研究前期实验表明，异位内膜中存在MFG-E8蛋白，故推测其参与调控内异症的发生。据此我们提出了实验假说： MFG-E8蛋白的异常表达可能促进细胞外基质重建和血管生成，导致内异症发生。为验证此假说，我们通过子宫内膜三维培养体系，采用RNA干扰，Western blot，免疫组化等手段，从分子、细胞、组织水平深入探讨MFG-E8在细胞外基质降解中的分子机制；通过血管内皮细胞研究细胞增生、粘附力，及新生血管形成，探讨了MFG-E8在异位内膜血管生成中的作用，进而阐明MFG-E8在异位内膜组织重建中的调控机理。本课题从MFG-E8蛋白失调这个新视点揭示异位内膜的形成机制，为内异症诊治提供新思路。