慢病毒介导miR-210修饰内皮祖细胞治疗脑缺血的作用及机制研究

项目名称： 慢病毒介导miR-210修饰内皮祖细胞治疗脑缺血的作用及机制研究

项目编号： No.81471246

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 曾丽莉

作者单位： 上海交通大学

项目金额： 70万元

中文摘要： 内皮祖细胞（EPCs）移植是治疗脑缺血热点策略，但移植细胞生存率低影响疗效，提高EPCs在缺血脑组织中的生存能力并发挥其生理功能是亟待解决的问题。我们前期研究发现缺血区microRNA-210（miR-210）增高具有强大的调节细胞抗缺氧凋亡及促血管神经再生作用。本课题拟利用慢病毒介导miR-210修饰EPCs（LV-miR-210-EPCs）这一新方法以达到增强EPCs生存能力和生理功能的目的，探索 1）与单纯EPC治疗相比，LV-miR-210-EPCs是否具有更有效的减小脑缺血小鼠梗死面积并改善其神经行为学的治疗作用；2）miR-210过表达是否能增加移植的EPC存活并促进其生理功能发挥；3）miR-210是否直接调控下游靶点NDUFA4、VEGF和BDNF而发挥抗缺血缺氧、抗细胞凋亡和促血管新生/神经再生作用。本研究有助进一步阐明脑缺血损伤发病机制，为缺血性卒中提供潜在治疗新靶点。

中文关键词： 脑缺血；内皮祖细胞；微小RNA；神经再生；血管新生

英文摘要： EPCs are regarded as the potential strategy for the repairing ischemic brain injury. However, researchers realize their undesirable treatment efficiency due to low survival rate of the transplanted stem cells. Therefore, it is of the most urgency to improve the EPCs survival and physiological function under hypoxia condition in the ischemic brain tissue. Our previous study showes that microRNA-210, a key hypoxia associated miRNA, possesses strong anti-apoptosis , and promotes angiogenesis and neurogenesis properties. However, EPCs overexpressing miRNA-210 improves the transplanted EPCs survival and physiological function is unknown. In present study, we use lentiviral vector to transduce miR-210 gene into EPCs to improve the EPCs survival. In the presence of increased miR-210 level in the ischemic region, both angiogenesis and neurogenesis are noticeably improved.The hypotheses include: 1) Compared to the EPC alone, if LV-miR-210-EPC have better action in decreasing infarct volume and improving long-term outcomes in mice with middle cerebral artery occlusion? 2) If EPCs overexpressing miRNA-210 improves the transplanted EPCs survival and physiological function? 3) If miR-210 playes a partial role in the direct signal regulation via NDUFA4，VEGF or BDNF? Our study is of great values in promoting a better understanding of post-ischemic injury repairing and pathophysiology, ultimately providing a potential novel therapeutic target for stroke.

英文关键词： stroke;EPC;microRNA;neurogenesis;angiogenesis