氧化应激是脑缺血-再灌注损伤的关键病理机制。T-LAK细胞源蛋白激酶（T-LAK cell originated protein kinase, TOPK）作为丝裂原活化蛋白激酶激酶MAPKK家族新成员，在正常成年脑组织的神经前体细胞增殖中特异表达，其在脑缺血-再灌注损伤中的变化、作用及机制，国内外未见报道。我们前期实验发现，活化的TOPK在急性脑梗死患者外周血中显著减少，而在大鼠脑缺血-再灌注模型脑组织中显著增加，两者变化趋势不同；初步研究发现，在PC12神经细胞中过表达TOPK增加抗氧化蛋白表达，抑制过氧化氢诱导的氧化应激损伤，而TOPK沉默加重细胞氧化损伤。本项目拟利用动物和细胞模型、分子生物学实验，明确TOPK在体内、体外对脑缺血-再灌注损伤的保护作用；阐明TOPK是否通过活化转录因子Nrf-2上调抗氧化蛋白表达，减少自由基生成发挥抗氧化作用，为脑缺血-再灌注损伤提供新的治疗靶点。

Oxidative stress is an essential pathological mechanism of cerebral ischemia- reperfusion injury. T-LAK cell originated protein kinase (TOPK), a new member of MAPKK family, was found to specifically express in neural precursor cells. However, it has not been reported both domesticly and abroad about the change, role and mechanism of TOPK in cerebral ischemia-reperfusion injury. Our previous research demonstrated a diverse tendency of activated p-TOPK that it decreased significantly in acute cerebral infarction patients, whereas obviously increased in brain tissues of rat models of cerebral ischemia-reperfusion injury. In preliminary studies, it is indicated that in PC12 cells over expression of TOPK gene will upregulate expressions of antioxidants and suppress oxidative stress injury to PC12 cells while silence of TOPK expression will aggravate oxidative injury. This project aims to confirm the neuroprotection effect of TOPK in cerebral ischemia-reperfusion injury both in vivo and in vitro by means of animal models and cells in culture, as well as subsquent molecular biological experiments. Besides, we will elucidate whether the antioxidant effect of TOPK is mediated by activation of transcription factor Nrf-2 to upregulate expressions of antioxidants and decrease generation of ROS, which would provide a new therapeutic target for cerebral ischemia-reperfusion injury in clinical application.