MBL与FGFR4相互作用促进系膜细胞EMT在IgA肾病中的作用及其分子机制的研究

项目名称： MBL与FGFR4相互作用促进系膜细胞EMT在IgA肾病中的作用及其分子机制的研究

项目编号： No.81500525

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 刘林林

作者单位： 中国医科大学

项目金额： 18万元

中文摘要： IgA肾病（IgAN）是最常见的肾小球肾炎，探讨其发生发展机制、寻找特异性治疗靶点至关重要。甘露糖结合凝集素（MBL）参与多种疾病发生发展，但在IgAN中的作用及机制尚不清楚。课题组前期研究发现尿MBL及在肾组织的沉积与IgAN更严重的临床病理表现及预后有关，并根据尿液与肾组织沉积的一致性推测MBL在肾组织局部发生异常反应导致严重肾损害；体外实验发现MBL能促进系膜细胞上皮间质转化（EMT），并能与系膜细胞膜蛋白FGFR4相互作用，从而推测MBL与FGFR4相互作用促进系膜细胞EMT而致严重肾损伤。本研究将在既往基础上，以人肾系膜细胞为工具细胞，证实MBL与FGFR4相互作用方式，建立IgAN鼠模型，通过体内试验探讨MBL与FGFR4相互作用促进系膜细胞EMT在IgA肾病中的作用，利用蛋白质谱分析高通量筛选FGFR4相互作用蛋白，并探讨具体功能途径，以期为IgAN治疗提供新靶点。

中文关键词： 上皮间质转化；甘露糖结合凝集素；成纤维细胞生长因子受体4；系膜细胞；IgA；肾病

英文摘要： IgA nephropathy (IgAN) is the most common form of gloemrulonephritis. It is crucial to investigate the mechanisms of the generation and development and to find specific therapeutic targets in IgAN. Mannose-binding lectin （MBL） is involved in various diseases, but its role in IgAN has not been defined. Our previous studies have administrated that the high levels of urinary MBL and the deposition of MBL in kidney were associated with more severe clinical and histological manifestations and prognosis of IgAN. According to the similar trends of urinary levels and histological deposition of MBL, we inferred that the abnormal reactions of MBL in kidney caused severe renal injury. The experiments in vitro demonstrated that MBL could promote epithelial-mesenchymal transition (EMT) in human mesangial cells and interact with fibroblast growth factor receptor 4 (FGFR4), a membrance protein of mesangial cells, so we can hypothesize that the interaction between MBL and FGFR4 may promote epithelial-mesenchymal transition in mesangial cells to cause the severe injury in kidneys. On the basis of previous studies, we will verify the way of the interaction between MBL and FGFR4 with human mesangial cells as a tool cell line. Rat models of IgAN would be built to investigate the role of the interaction between MBL and FGFR4 promoting epithelial-mesenchymal transition in mesangial cells in IgA nephropathy. A high thoughput screening with proteomics and mass spectrometry analysis will be performed to define the interacting proteins with FGFR4. Moreover, we will further investigate the pathway of interaction between proteins to supply new therapeutic targets for IgAN.

英文关键词： Epithelial-mesenchymal transition;mannose binding lectin;fibroblast growth factor receptor 4;mesangial cell;IgA nephropathy