UNC5H2受体介导Netrin-1蛋白诱导脑缺血后血管再生的分子机制研究

脑缺血是常见的脑损伤原因，可引起神经元坏死，导致瘫痪和死亡。本课题组前期研究发现，Netrin-1可显著增加卒中动物脑梗死周围区血管再生，并改善卒中动物运动功能。但其分子机制尚无定论。现有观点认为Netrin-1与受体UNC5H2结合后阻断DAPk信号通路，从而减少内皮细胞凋亡。但增生的内皮细胞通过什么机制完成后续的细胞粘附和细胞迁移过程，尚不明确。我们提出假说：Netrin-1与UNC5H2结合后，启动Src-FAK-Paxillin信号通路，促进细胞粘附和细胞迁移，帮助增生的血管内皮细胞形成新的毛细血管网。为验证这一假说，我们拟进行细胞实验和动物实验，采用特异性阻断剂、RNAi、基因敲除等干预手段，检测Src-FAK-Paxillin信号通路的变化和对Netrin-1作用的影响。本研究有望为缺血性脑血管病的治疗提供新的理论基础和治疗靶点，为改善患者预后带来新的希望。

Brain ischemia is a common cause of brain injury, which can cause neuron necrosis, paralysis and death. In previous study our group found that Netrin-1 can significantly promote angiogenesis in ischemic area and improve motor functions in stroke animal. However, the molecular mechanism remains unclear. Current opinion is that Netrin-1 binds to its receptor, UNC5H2, and blocks the DAPk signaling pathway, so as to inhibits apoptosis. But it is not clear how the proliferating endothelial cells adhere and migrate? We hypothesize that Netrin-1 binds to UNC5H2 and activates Src-FAK-Paxillin signaling pathway, which can boost adhesion and migration. To validate this hypothesis, we plan to conduct cell culture and animal experiments, using specific blocker, RNAi, gene knockout to detect the change of Src-FAK-Paxillin signaling pathway and its impact on Netrin-1's effect. Hopefully our project can provide new theories and therapeutic targets for ischemic vascular diseases and help improve the prognosis of the patients.