基于Wnt/β-catenin的PAF调控脑缺血后血管内皮功能的机制研究

血小板活化因子（PAF）是加重脑缺血损伤的重要因素，通过与其受体（PAFR）结合而发挥生物学作用。有关PAF对脑缺血后血管内皮细胞功能的影响及机制研究未见报道。本项目基于良好的前期工作，提出“脑缺血后PAF/PAFR通过Wnt/GSK3β/β-catenin通路介导血管内皮细胞屏障及增殖功能障碍”的科学假说。拟借助PAFR拮抗剂（XQ-1H）及PAFR-/-小鼠，研究PAF对小鼠脑缺血后急性期血脑屏障完整性，及恢复期血管新生的影响，明确PAF对血管内皮细胞紧密连接、增殖及迁移的影响。在此基础上，研究PAF通过活化小胶质细胞，释放炎症因子，进一步损伤内皮细胞及神经元功能的作用。最后，研究PAF是否通过Wnt/β-catenin通路，破坏血管内皮细胞间紧密连接，抑制内皮激活、增殖、迁移，并阐明其机制。研究结果将为PAFR拮抗剂的机制研究提供依据，为以血管内皮为靶点的抗脑缺血药物研究提供思路。

Platelet activating factor (PAF), which interacts with its specific platelet activating factor receptor (PAFR) and elicits a variety of biological functions, is a critical factor in aggravating the injury of ischemic stroke. However, the effect of PAF in regulating the vascular endothelial cell function and the underlying mechanism remains to be elucidated. Based on our previous study, we propose scientific hypothesis that PAF/PAFR mediates vascular endothelial barrier and angiogenesis dysfunction via interfering Wnt/GSK3β/β-catenin signal pathway after ischemic stroke. Firstly, to clarify the effect of PAF on the blood brain barrier integrity and angiogenesis during the acute/recovery phase of stroke, PAFR antagonist (XQ-1H) and PAFR-/- mice were used to investigate the tight junction expression, migration and proliferation of cerebrovascular endothelial cell. Secondly, the effect of PAF in regulating microglia activation was studied to illuminate its possible indirect effects in regulating endothelial and neuronal function. Lastly, the relationship between PAF and Wnt/GSK3β/β-catenin signal pathway is explored to elucidate the regulatory mechanism of PAF. This study could provide experimental basis for mechanism research of PAFR antagonist, and open a new approach for the development of anti-stroke drugs targeting to endothelial cells.