NFATC2IP/IL-4信号通路参与家族性膜性肾病的机制研究

膜性肾病（MN）是引起成人肾病综合征最常见的病因之一且预后通常较差，其发病机制复杂且尚不明确。课题组对MN家系样本进行全基因组测序寻找到NFATc2IP的致病突变，其突变导致其与TRAF2蛋白的互作减少，同时增加IL-4的转录活性；免疫组化结果显示MN患者肾小球有大量IL-4表达。因此课题组推测NFATc2IP/TRAF2/IL-4通路是家族性MN发生的主要因素。本研究拟利用酵母双杂交鉴定出NFATc2IP正常型和点突变的差异互作蛋白，同时借助knockin小鼠、AAV过表达技术和膜性肾病模型在动物水平明确NFATc2IP和点突变的作用和分子机制，最后在动物水平明确IL-4是点突变引起膜性肾病发生的重要细胞因子。通过以上研究，本项目将明确系统揭示NFATc2IP参与家族性膜性肾病发生的分子机制，为发展基于NFATc2IP和相关分子为靶标的膜性肾病的诊断、干预或治疗新方法打下基础。

Membranous nephropathy (MN) is one of the most common causes of adult nephrotic syndrome and its prognosis is usually poor. Its pathogenesis is still complex and unclear. We had performed genome-wide sequencing of MN family samples, and identified the pathogenic mutation of NFATc2IP. The mutation leads to a decrease in the interaction between NFATc2IP and TRAF2, and increases the transcriptional activity of IL-4. Immunohistochemistry results showed that a large amount of IL-4 accumulated in the glomeruli of three MN patients compared to healthy donor. Therefore, our group speculates that the NFATc2IP/TRAF2/IL-4 pathway is involved in the occurrence of the familial MN. This study will identify specific interacting proteins with normal NFATc2IP or point mutant by yeast two-hybrid, and determine the role and molecular mechanism of NFATc2IP and the mutation at the animal level by means of knockin mice, AAV overexpression technique, and membranous nephropathy model. We will also systematically demonstrate IL-4 as a major pathogenic factor of MN. We believe that this project will systematically elucidate the molecular mechanism of NFATc2IP in the development of membranous nephropathy, which will provide new clues for developing new diagnosis and/or treatment strategy for membranous nephropathy.