免疫性肾小球疾病（IMGN）是我国最常见的慢性肾脏病，其发病机制尚未完全阐明。我们通过大数据挖掘和系统分析发现“炎症反应网络”是IMGN的共同通路；整合表达谱及eQTL等数据，提示WWP2是调控“炎症反应网络”簇基因表达的中心环节。WWP2是泛素化修饰的关键酶，预实验发现其在IMGN中表达增加，且主要定位于足细胞和浸润的巨噬细胞，WWP2缺陷可减轻膜性肾病小鼠肾损伤。由此设想：WWP2通过泛素化修饰底物蛋白，调控“炎症反应网络”簇基因表达，加剧肾脏区域免疫炎症反应，启动和促进免疫炎症介导的肾损伤，最终导致肾小球硬化。本研究拟应用足细胞、巨噬细胞条件性WWP2敲除小鼠制备膜性肾病和狼疮性肾炎模型，结合前期应用计算机辅助药物筛选平台获得的WWP2候选小分子抑制剂，探讨WWP2介导的泛素化修饰在IMGN中的作用及其分子机制，在此基础上筛选WWP2特异性抑制剂，从而探求IMGN精准靶向治疗的措施。

Immune-mediated glomerular nephropathy (IMGN) serve as the most common chronic kidney disease (CKD) in China. However, the pathogenic mechanism of IMGN is still unclear and the specific therapy on IMGN is also absent. Thus, to better understand the pathogenesis of IMGN is of importance for the development of specific targets and effective therapies. Through the systemic analysis of big data, we found that the “inflammation-network” accounts for the common pathogenic pathway of immune glomerular diseases. Further analysis via the expression profiling and eQTL revealed that WWP2 is the key controller of this “inflammation-network” in IMGN. WWP2 is a key enzyme for the ubiquitination of proteins. Our preliminary studies demonstrated that WWP2 was upregulated in the podocytes and infiltrated macrophages in the kidneys of IMGN patients, suggesting an important role of WPP2 in IMGN. According to the information from big data analysis and the preliminary results, we hypothesized that WWP2 could regulate the expressions of proinflammatory genes of “inflammation-network” via the ubiquitin modification of substrate proteins to promote the immune inflammatory response in kidney, leading to the inflammatory renal injury and glomerulosclerosis. In this proposal, we will employ the animal models of membranous nephropathy and lupus nephritis produced using podocyte- and macrophage-specific WWP2 KO mice and in vitro cell models to fully investigate the role of WWP2 in the pathogenesis of IMGN, as well as the underlying mechanisms. Meanwhile, we will discover the specific small molecular inhibitors of WWP2 using the candidates of small molecules screened through a computer-assisted drug screening platform. Therefore, this study will not only reveal a novel pathological mechanism of IMGN, but also shed light on the development of new therapeutic strategies treating immune glomerular diseases in clinic.