脑缺血后再灌注期氧供给重新建立使缺血组织产生大量过氧化物。如何防治此时脑损伤不但是临床关注焦点，也依赖对脑缺血再灌注病理生理机制和信号传导途经了解。我们发现缺血与再灌注均间接激活EGF受体，但其两个主要信号传导通路PI3K/AKT和MAPK/ERK活性截然不同。缺血期AKT激活，ERK无变化；而再灌注期则反之。由此猜测：缺血期AKT高度激活抑制MAPK/ERK上游Raf；而再灌注期产生过氧化物引起内质网应激，后者通过GRP78和/或mTORC1负性调节AKT磷酸化，从而消除AKT对Raf抑制。由于AKT和ERK在细胞损伤发挥作用不同，缺血期与再灌注期两个信号传导通路转换和相互作用可能与脑缺血/再灌注引起脑损伤密切相关。本项目将对脑缺血/再灌注对两条信号传导通路影响和两条通路相互作用机制做系统研究。并针对信号通路的变化采用不同干扰手段，观察其对脑损伤影响，为脑缺血/再灌注临床治疗提供新思路。

It is well known that a large amount of reactive oxygen species (ROS) is produced during reperfusion after brain ischemia. Intervention of cell damage during this period of time may be critical for the treatment of brain ischemia in clinic. Recently, we have found that EGF receptor is transactivated in both ischemia and reperfusion periods. However, the two intracellular signal pathways of EGF receptor, PI3K/AKT and MAPK/ERK1/2 are stimulated differently in the two time periods. During ischemia, AKT, but not ERK1/2 is phosphorylated, but it is reversed by reperfusion. ERK1/2 phosphorylation is actually dependent on reperfusion. Furthermore,during the period of brain ischemia it phosphorylated Raf-1 on Ser-259 which can decrease Raf-1 activity. We hypothesized that during the period of brain ischemia AKT may regulated the MAPK/ERK1/2 pathway through phosphorylation of Raf-1 at Ser-259 regulatory site. During the period of reperfusion, the production of ROS causing endoplasmic reticulum stress (ERS) is the main reason for supression of PI3K/AKT signaling pathways through the interaction between glucose-regulated protein 78 (GRP78) and AKT or hyperactivation of the mammalian target of rapamycin complex 1 (mTORC1). Then it weaken the inhibition of AKT to MAPK/ERK1/2 signaling pathways.The different activities of and interaction between the two signal pathways may be the underlying mechanisms of cell damage during brain ischemia/reperfusion. In this study, we will focus on the regulation of these signal pathways in brain ischemia/reperfusion and their role in cell injury. This information will eventually contribute the new therapeutic strategies for brain ischemia in clinic.