COUP-TF1基因调控激肽原1参与增生性玻璃体视网膜疾病的机制研究

项目名称： COUP-TF1基因调控激肽原1参与增生性玻璃体视网膜疾病的机制研究

项目编号： No.81470648

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 于靖

作者单位： 同济大学

项目金额： 73万元

中文摘要： 增生性玻璃体视网膜病变 (PVR) 是孔源性视网膜脱离手术失败的最主要原因。本课题组首次发现激肽原1(KNG1)是预告PVR严重程度和预后的候选血清分子标志物，而COUP-TF1是重要的调控基因。但是调控KNG1升高的机制以及KNG1发挥作用的机制尚不明确。文献显示，COUP-TF1可调节激肽释放酶结合蛋白(KBP)的基因表达。因此，提出假说，COUP-TF1通过调节KBP使KNG1表达增加，KNG1通过PKC-ERK 信号通路抑制PVR。为了验证这一假说，本课题拟应用PVR动物和细胞模型，采用基因敲除、siRNA干扰、慢病毒载体转染等方法，从分子、细胞、组织和动物整体水平等多方面探讨COUP-TF1调控KNG1表达增加的机制，明确KNG1促进PVR发展的相关作用以及其作用的信号通路。本课题的完成将有助于从基因调控水平揭示PVR的发病机制，并为PVR的药物治疗提供新靶点。

中文关键词： 增生性玻璃体视网膜病变；视网膜；视网膜色素上皮细胞；激肽原1

英文摘要： Proliferative vitreoretinopathy (PVR) is the leading cause of retinal detachment (RD) surgery failure. Our previous proteomic study firstly documented that kininogen 1 (KNG1) was the candidate serum biomarker, which could predict the severity and prognosis of PVR. Chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) was the critical gene in PVR. However, the mechnaism of the regulation of KNG1 increased and the signal pathway of KNG1 worked was not known well. The references presented that COUP-TF1 could regulate kallikrein-binding protein (KBP). Therefore, we hypothesized that COUP-TF1 may regulate KBP to increase the expression of KNG1, which may inhibit progression of PVR via PKC/ERK signal pathway. To tset the hypothesis, the methods of gene knockout, siRNA interfere and slow virus vector transfection would be used into the mice PVR models and PVR cell models. The mechnaism of the regulation of KNG1 increased, the contribution of the KNG1 involved in PVR and the signal pathway of KNG1 would be investigated from the levels of molecular,cell, tissue and animal.This study would provide advanced recognition of the pathogenesis of PVR in the gene level and the new targets of anti-PVR biological drug.

英文关键词： proliferative vitreoretinopathy;retina;retinal pigment epithelium;kininogen1