低氧处理的血管内皮组细胞通过抑制“NLRP3炎症小体-线粒体损伤”正反馈环路减缓焦亡以治疗脑I/R损伤

脑缺血再灌注（I/R）损伤的治疗是卒中康复领域的关键科学问题。有文献报道，I/R后线粒体的损伤，NLRP3炎症小体的高表达及GSDMD介导的细胞焦亡是其重要改变。我们前期研究也发现，I/R损伤可导致大鼠脑组织NLRP3水平上调。有研究指出血管内皮祖细胞（EPCs）可以保护线粒体形态，减少ROS及炎症相关因子的表达。我们发现低氧培养的内皮祖细胞（Hypoxia-EPCs）增殖能力更强，且目前在脑I/R中尚无研究“NLRP3炎症小体-线粒体损伤”正反馈环路与小胶质细胞焦亡的关系，由此我们提出：Hypoxia-EPCs可通过抑制上述正反馈环路减缓小胶质细胞焦亡以治疗脑I/R损伤。本课题采取RNA干扰，基因敲除及Mito TEMPO等手段，从分子、细胞以及动物整体水平等多方面对科学假设进行验证，为脑I/R的治疗提供潜在的治疗靶点。

The treatment of cerebral ischemia-reperfusion (I/R) injury is a key scientific issue in the field of stroke rehabilitation. It has been reported that the damage of mitochondria, the high expression of NLRP3 inflammasome and the cell pyroptosis mediated by GSDMD are the important changes of I/R. Our previous study also found that OGD/R injury can lead to up-regulation of ROS and NLRP3 levels in PC12 cells. Studies have shown that vascular endothelial progenitor cells (EPCs) can protect mitochondrial and reduce the expression of ROS and inflammation-related factors. We found that the proliferation ability of hypoxia preconditioned endothelial progenitor cells is stronger, and the existence of "NLRP3 inflammatory corpuscle-mitochondrial damage" positive feedback loop and the relationship between the microglia pyroptosis is unclear, so we assume that: hypoxia preconditioned endothelial progenitor cells can reduce microglia by inhibiting the positive feedback loop to treat cerebral I/R injury. In this study, RNA interference, gene knockout and MitoTEMPO will be used to verify scientific hypotheses at the molecular, cellular and animal level, providing potential therapeutic targets for the treatment of ischemic stroke.