肾小球滤过屏障破坏是糖尿病肾病（DN）的特征性表现。先天免疫在DN发病机制中起重要作用。足细胞作为滤过屏障的重要组成部分，兼具免疫细胞特性。先天免疫反应被激活可诱导细胞焦亡，但其具体分子机制尚不清楚。本课题组前期研究发现DN中足细胞先天免疫重要组分NLRP3炎症小体过度活化通过GSDMD介导细胞焦亡，然而NLRP3活化的上游调节机制不明。本课题组前期预实验发现DN小鼠肾小球存在特异性环状RNA（circRNA）表达谱。根据生物信息学、FISH、RIP等预实验结果推测DN中异常表达的circPHF12可能通过竞争性抑制miRNA-223-3p来调控NLRP3活性，从而影响足细胞焦亡。本项目拟以DN足细胞NLRP3异常活化为切入点，揭示circPHF12调控NLRP3活化致DN的机制，明确其作为DN评价新指标与DN肾损害的相关性，形成靶向干预circPHF12防治DN的新策略。

Diabetic nephropathy (DN) is characterized by the disruption of glomerular filtration barrier. Innate immunity plays an important role in DN. Podocytes, highly specialized glomerular epithelial cells of filtration barrier, possess the property of immune cells. Pyroptosis can be induced by the activation of innate immunity, but the detail mechanisms are still unclear. Our previous studies found that NLRP3 inflammasome overactivation was involved in podocyte pyroptosis by regulating GSDMD pathway. But the upstream regulatory mechanisms of NLRP3 remain unclear. Our previous microarray studies detected the expression profiles of circular RNA (circRNA) in DN mouse glomeruli, and the expression of circPHF12 increased significantly in DN. circPHF12 can bind miRNA-223-3p according to bioinformatics, fluorescence in situ hybridization and RNA immunoprecipitation detections, which may mediate podocyte pyroptosis through the downstream target molecule NLRP3. Based on previous studies, we propose to focus on podocyte NLRP3 inflammasome overactivation in DN, and systematically explore the mechanisms of circPHF12 regulating NLRP3 inflammasome activation, which may provide new insights in understanding the disease pathogenesis and identify novel therapeutic targets for DN.