JAK/STAT信号通路异常在重症药疹肾脏损伤中作用的研究

项目名称： JAK/STAT信号通路异常在重症药疹肾脏损伤中作用的研究

项目编号： No.81460470

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 于均峰

作者单位： 新疆医科大学

项目金额： 40万元

中文摘要： 肝肾严重损伤是重症药疹患者死亡的主要原因之一，但是仅用Ⅳ型变态反应不能完全解释其病理机制。本研究是在前期研究的基础上提示药疹存在细胞免疫反应异常的基础上，通过检测不同时期重症药疹患者体内免疫功能紊乱的指标和肾脏损伤指标，探讨免疫反应异常与肾脏损伤的时间-效应关系；构建JAK/STAT信号通路中的抑制性蛋白pcDNA3.1-SOCS1质粒转染至人HK-2细胞与药物特异性T细胞及致敏药物共培养，检测HK-2细胞的增殖与凋亡，培养液中细胞因子的水平和细胞提取液信号通路蛋白的含量，探讨药物刺激下效应T细胞介导的JAK/STAT信号通路异常参与肾脏损伤的机制；用与不用JAK拮抗剂AG-490时，通过动物模型研究外周血T细胞的亚群数量、分泌的细胞因子水平、肾脏损害及肾组织中JAK/STAT信号通路蛋白的表达，深入研究药物引起的免疫功能紊乱以及JAK/STAT信号通路异常在重症药疹肾脏损伤中的作用机制。

中文关键词： JAK/STAT；重症药疹；药物特异性T细胞；信号通路

英文摘要： Serious liver and kidney damage is one of the main causes of death in patients with severe drug eruption，type IV allergy reaction can not fully explain the pathological mechanisms of serious liver and kidney injury. Our previous study have suggests that the immune system dysfunction is involved in the pathogenesis of drug eruption. In the present study, investigate the relationship between immunoreaction disorder with kidney damage by testing immunoreaction dysfunction relevant indexes and kidney damage in patients with severe drug eruption based on different periods. Construction the plasmid of pcDNA3.1-SOCS1 and transfection into the HK-2 cell, and then cultured the HK-2 cell with the drug specific T cells. Detect the relevent quotas with HK-2 damage.Such as: HK-2 cell surface receptor expression, inflammatory cytokines, cell proliferation and apoptosis of HK-2 cells.To explore drug specificity of JAK/STAT passway and its mediated mechanisms involved in the kidney damage, we detect the protein level of the p-JAKs and p-STATs in JAK/STAT signalling passway.At last, by the animals model with and without the JAKs antagonist AG-490, detect the levels of inflammatory cytokines, PBMC,kidney ultra-structure alteration and protein levels to explore possible role of immunoreaction dysfunction in kidney damage by activated JAK/STAT signalling pathway. The objective of this research will further enrich the pathogenesis of severe drug eruption, and provide new ideas for prevention and therapeutics of liver and kidney damage of severe drug eruption.

英文关键词： JAK/STAT;severe drug eruption;drug mediated special T cell;signaling passway