Irisin通过线粒体自噬/ROS/NLRP3信号轴调控巨噬细胞极化对移植肾DGF的防治作用及机制研究

移植肾DGF是肾移植术后最常见的并发症，是肾移植成功的重大障碍，深入研究移植肾DGF的发生机制及寻找有效防治措施是当前临床上亟待解决的关键问题。Irisin是新近发现的对炎症免疫损伤具有保护作用的效应多肽。申请人前期研究发现移植肾DGF受者血清Irisin水平明显降低且和肾功能线性负相关，预实验提示外源性Irisin能减少DGF肾脏炎性损伤及免疫细胞浸润，其效应机制可能与增强线粒体自噬、ROS/NLRP3负向调控及巨噬细胞极化有关。最新研究也表明巨噬细胞在移植肾免疫激活中发挥重要作用并受NLRP3调节。本项目拟在前期研究基础上，进一步研究Irisin是如何通过增强线粒体自噬、负向调控NLRP3活化减少肾小管细胞坏死，并揭示NLRP3调控巨噬细胞极化抑制适应性免疫激活的机制，进一步阐明移植肾DGF发生、免疫反应增加及影响长期预后的机制，为临床防治移植肾DGF提供理论依据及新靶向治疗策略。

DGF is the most common early complication after renal transplantation, which is a major obstacle to the success of renal transplantation. It is the key problem to study the mechanism of DGF and find effective prevention and treatment measures. Irisin is a newly discovered protein with protective effect on inflammatory immune injury. Previous studies of the applicant found that the serum irisin level of DGF recipients was significantly decreased and negatively correlated with renal function. Preliminary experiments suggested that exogenous irisin could reduce renal inflammatory injury and immune cell infiltration in DGF recipients, and its mechanism might be related to the enhancement of mitochondrial autophagy, ROS / NLRP3 negative regulation and macrophage polarization. The latest studies also showed that macrophages were activated in the transplanted kidney It plays an important role and is regulated by NLRP3. On the basis of previous studies, this project intends to further study how irisin can reduce tubular cell necrosis by enhancing mitochondrial autophagy and negatively regulating NLRP3 activation, and reveal the mechanism of NLRP3 regulating macrophage polarization and inhibiting adaptive immune activation, so as to further clarify the mechanism of DGF occurrence, increased rejection and long-term prognosis of transplanted kidney, so as to provide reference for clinical prevention and treatment of DGF Theoretical basis and new targeted therapy strategy.