RGMa在缺血性脑卒中tPA治疗诱导的血脑屏障破坏和脑微血管血栓形成中的作用及机制研究

tPA静脉溶栓治疗是缺血性脑卒中的首选治疗方法，但tPA的非溶栓作用会导致部分接受tPA治疗的患者发生脑梗死出血转化或神经功能恢复不良。发生前述两种情况的主要原因分别是tPA增加MMP-9表达促进血脑屏障破坏和tPA增加PAI-1表达促进脑微血管血栓形成，但相关调控机制及干预靶点尚不明确。我们预实验发现缺血性脑卒中tPA治疗后外周血和脑缺血区域RGMa表达增多，前期研究提示RGMa活化RhoA和Smad2/3，国外研究报道RhoA活化促进MMP-9表达、Smad2/3活化促进PAI-1表达。因此本项目拟通过临床研究、体内和体外实验，验证以下科学假设：缺血性脑卒中tPA治疗诱导RGMa表达增多，RGMa在脑血管内皮细胞上通过RhoA/MMP-9促进血脑屏障破坏，通过Smad2/3/PAI-1促进脑微血管血栓形成。RGMa可能是tPA溶栓后神经保护治疗的关键靶点。本研究将为卒中治疗提供新思路。

Intravenous tPA thrombolysis is the current first choice treatment of ischemic stroke. However, the non-thrombolytic effects of tPA would induce some patients who receive tPA treatment develop a hemorrhagic transformation or exhibit poor recovery of neurological function despite successful thrombolysis. The main reason for hemorrhagic transformation is that tPA-induced MMP-9 expression promotes disruption of blood-brain barrier. And the main reason for poor recovery of neurological function is that tPA-induced PAI-1 expression facilitates brain microvascular thrombosis. However, the mechanisms and therapeutic target of them are unclear. Our preliminary tests found that tPA treatment increased RGMa expression in the plasma and in the brain ischemic area after stroke. Our previous studies suggested that RGMa activated RhoA and Smad2/3. It has been reported that RhoA activation facilitated MMP-9 expression and Smad2/3 activation promoted PAI-1 expression. Therefore, we plan to make use of clinical research, in vivo experiments, and in vitro experiments to confirm the following hypothesis: After ischemic stroke, tPA treatment increases RGMa expression. RGMa promotes blood-brain barrier disruption through RhoA/MMP-9 and facilitates brain microvascular thrombosis through Smad2/3/PAI-1 in brain endothelial cells. RGMa may be the key target for neuroprotection after tPA thrombolysis. This study would provide new ideas for the treatment of stroke.