miR-539-5p在CXCR7介导的内皮细胞间质变（EndMT）及脉络膜纤维化中的作用及机制研究

脉络膜新生血管（CNV）最常见于年龄相关性黄斑变性和病理性近视，是致盲的直接原因。新近发现细胞转分化是器官纤维化的重要成因，我们前期研究发现脉络膜血管内皮细胞间质转化（EndMT）参与脉络膜纤维化的形成，而CXCR7基因沉默能抑制TGF-β1诱导的EndMT，但具体机制尚不明确。本课题拟以人脉络膜血管内皮细胞为研究对象，通过基因沉默、过表达技术及分子生物学手段，全面探索miR-539-5p的靶基因CXCR7、ZEB1和Smad2对miR-539-5p表达水平的影响以及靶基因间的相互调控，阐明CXCR7对EndMT的影响是基于miR-539-5p介导的竞争性内源性RNA(ceRNA)网络调控机制。我们将进一步采用激光诱导的CNV动物模型，明确CXCR7基因敲除及miR-539-5p过表达对CNV纤维化形成的作用。我们旨在通过本项研究为靶向治疗CNV导致的脉络膜纤维化打下坚实的理论基础。

Choroidal neovascularization (CNV) is most common in age related macular degeneration (AMD) and pathologic myopia, which ultimately lead to irreversible blindness. Although anti-vascular endothelial growth factor (anti-VEGF) therapy has become a standard treatment for CNV, unsuccessful treatment outcomes have often been attributed to the progression of fibrous plaque/disciform scar. Cell transdifferentiation has been confirmed as an important cause of organ fibrosis. In our previous study, we found that endothelial-derived cells contributed to subretinal fibrosis formation through endothelial to mesenchymal transition (EndMT) and CXCR7 silencing significantly decreased Endo-MT induced by transforming growth factor-β1 (TGF-β1), but the exact mechanism remains unclear. This project aims to explore the regulatory effects of miR-539-5p target genes CXCR7, ZEB1 and Smad2 on the expression of miR-539-5p, and the regulation of target genes among each other by using the means of gene silencing and over-expressing intervention on human choroid endothelial cell (HCEC) in vitro. Moreover, we will elucidate the mechanism of CXCR7 regulates EndMT is based on miR-539-5p-mediated competing endogenous RNA (ceRNA) network. In vivo experiments, an animal model of CNV was induced by laser photocagulation, and then a variety of molecular biology methods will be use to explore the role of CXCR7 knocked out and miR-539-5p over-expression on the formation of fibrosis in CNV. We hope that these achievements can contribute to the theory and practical application for the development of new drugs on blindness caused by fibrosis in CNV.