经血源性子宫内膜干细胞来源外泌体降低免疫毒素HP38引起的急性肝损伤的分子机制及其应用研究

免疫毒素在临床实验中具有良好的抗肿瘤效果，但其脱靶效应导致的毒副作用限制了免疫毒素的安全给药剂量。降低免疫毒素的脱靶效应从而提高其治疗窗口，对于此类药物的研究开发具有指导意义。前期研究我们发现，经血源性子宫内膜干细胞（MenSCs）来源的外泌体在体外能够降低免疫毒素HP38对于肝脏细胞的毒性，在小鼠体内能够降低ALT和AST含量及炎症因子的表达，同时外泌体能够增加小鼠对于免疫毒素的最大耐受剂量。我们推测，MenSCs来源的外泌体通过降低肝脏炎症水平及促进肝脏细胞增殖从而降低免疫毒素引起的小鼠急性肝损伤。本项目拟通过分析外泌体中细胞因子和miRNA的表达，结合免疫毒素给药后小鼠肝脏炎症因子、凋亡因子和细胞增殖相关蛋白的表达变化，探讨外泌体降低免疫毒素引起的急性肝损伤的分子作用机制。最后，评价免疫毒素联合外泌体在小鼠移植瘤模型中的抗肿瘤效果，为免疫毒素在临床实验中的应用提供重要的参考依据。

Immunotoxin has good anti-tumor effect in clinical trials, while off-target effects restrict its clinic doses. It has guiding significance for the research and development of such drugs to reduce the off-target effects of immunotoxin and improve its treatment window. In previous studies, we found that exosomes derived from MenSCs can reduce the damage of immunotoxin HP38 to liver cells in vitro, and reduce the level of ALT and AST and the expression of inflammatory factors in vivo. At the same time, MenSC-exosomes can increase the maximum tolerance dose of mice to immunotoxin. We speculate that exosomes derived from MSCs can reduce the inflammation level and promote cell proliferation in liver, thereby relieving the acute liver injury caused by immunotoxin. This project intends to analyze the expression of cytokines and miRNA in exosomes and investigate the molecular mechanisms of exosomes relieving the acute liver injury induced by immunotoxin, through analysis of inflammatory, apoptosis and cell proliferation related proteins in mice liver after treated with immunotoxin. Based on this, we will evaluate the antitumor effect of immunotoxin combined with exosomes in mice xenograft model, and ultimately provided an important reference for the application of immunotoxin in clinical trials.