岩大戟内酯B通过调控TWEAK/Fn14介导通路治疗狼疮肾炎的作用机制研究

狼疮肾炎（LN）是系统性红斑狼疮（SLE）常见且严重的并发症。肿瘤坏死因子样弱凋亡诱导因子（TWEAK）及其特异性受体成纤维细胞生长因子诱导分子14（Fn14）在SLE等自身免疫疾病及急慢性肾损伤中起重要作用。课题组前期对狼毒大戟研究发现，其活性成分岩大戟内酯B（JB）通过下调TWEAK发挥抗肾脏炎症和纤维化的作用。由此，本课题提出“JB通过调控TWEAK/Fn14介导通路治疗LN”的科学假说。本课题拟利用前期成功建立的pristane诱导狼疮样小鼠模型，考察JB对LN的治疗作用；利用重组TWEAK诱导多种细胞模型，观察JB对炎症及纤维化的作用及对TWEAK/Fn14下游NF-κB通路和TGF-β/Smad通路的调控机制；从而阐明JB治疗LN的作用机制，为治疗LN活性先导化合物和药物新靶点的发现奠定基础，为丰富中医药治疗LN经验和开发传统中药提供依据。

Lupus nephritis (LN) is a common and severe complication of systemic lupus erythematosus (SLE). Tumor necrosis factor like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible molecule 14 (Fn14) play important roles in autoimmune diseases and acute and chronic kidney injury. We have done numerous research on Euphorbia fischeriana, and have found its active component, Jolkinolide B (JB), exerts protective effects against kidney inflammation and fibrosis by downregulating TWEAK. Thus, we hypothesize that JB treats LN via regulating TWEAK/Fn14 pathway. In this study, we planned to investigate the therapeutic effect of JB on LN by using the lupus-like mouse model induced by pristane. Then we will ise multiple cell models induced by recombinant TWEAK, and assess whether JB has protective effects against kidney inflammation and fibrosis and regulates the downstream pathway of TWEAK/Fn14, NF-κB pathway and TGF-β/Smad pathway. In conclusion, the present study will explain the mechanism of JB in the treatment of LN, provide prospect for discovering lead compounds and new drug targets for LN therapy, and provide perspectives for enriching the experience of traditional Chinese medicine treatment of LN.