Shh调节纤溶活性在脑梗死治疗中的作用及机制研究

Fibrinolytic imbalance is one of the main reasons that cerebral infarction comes on. It has been reported that the fibrinolytic activity is suppressed in ischemic individuals, it is a risk factor influencing prognosis. The fibrinolytic activity regulated by critical equilibrium between tissue-plasminogen activator (t-PA) and its endogenous inhibitor, plasminogen activator inhibitor 1 (PAI-1), An imbalance between t-PA and PAI-1 is thought to be a key event in the transition from physiological to pathological conditions in some thrombotic diseases. It is has been clarified that sonic hedgehog (Shh) promotes t-PA expression and reduces PAI-1 expression. This role is fascinating, it implies that Shh could regulate the fibrinolytic imbalance resulting from stroke attack. Unfortunately, little is known about the effect of Shh on cerebral infarction by regulating t-PA and PAI-1 expression. Hence, one of goals in this project is to elaborate the potential therapeutic effect of Shh on stroke. Similarly, the exact regulatory mechanisms of these two proteins by Shh are still unclear. According to the previous studies and our research, we hypothesized that the LDL receptor-related protein-1 (LRP-1) is the critical mediatory protein, and a new pathway including Shh/LRP-1/t-PA and PAI-1 is predictable. Hence, the other goal in this project is to validate this hypothesis. In this project, genetic, molecular and cell biology techniques will be performed. Our results will provide a new idea for prevention and treatment of cerebral infarction.

纤溶活性下降是脑梗死发生和发展的重要原因，t-PA和PAI-1表达比例失调是影响纤溶活性的关键。已知Shh能促进t-PA的表达，并抑制PAI-1的表达，其结果可激活内源性纤溶系统，加速血栓溶解。我们前期研究发现内源性纤溶系统激活能显著减少梗死面积且不增加继发性出血的风险，因此，此作用在脑梗死治疗中有重要意义，但未见相关报道。目前对Shh调节t-PA和PAI-1表达的机制还不清楚，且调节机制独立于Shh经典信号通路。我们结合以前的研究和我们的前期研究结果，提出LRP-1是重要的中继蛋白，且存在由Shh/LRP-1/t-PA、PAI-1组成的新的信号通路。由此，本课题利用分子及细胞生物学，基因组学和免疫学等技术，综合研究Shh调节脑梗死后t-PA和PAI-1表达的作用及意义，并探索Shh通过LRP-1调节t-PA和PAI-1表达的机制，以期为脑梗死的研究提供新的思路和治疗靶点。