miR-210对缺血性脑损伤的治疗作用及机制研究

Known as a recognized Hypoxia marker, miR-210 was significantly increased after hypoxic stimulus. Futher more, the level of miR-210 was also found to be improved after focal cerebral ischemia. Some studies proved that miR-210 was involved in cerebral ischemic injury related pathophysiologic process, such as mitochondrial energy metabolism, cell survival, cell cycle, DNA repair and angiogenesis. Based on these findings, we assumed that the regulation of miR-210 may help to improve the prognosis of cerebral ischemia. The present study was to clear part of its regulatory mechanisms in the pathophysiology of ischemic brain injury. Then, we plan to use multipotent mesenchymal stromal cells (MSCs) derived exosomes to mediate tansfer of miR-210 and evaluate their therapeutic effects on ischemic brain injury. The miR-210 cargo exosomes can get through BBB easily, and stably transfer miR-210 to specific targets in brain, thus control the downstream target gene network. In this study, we try to futher assess the effectiveness and the targeting of exosomal miR-210 treatment in vivo and vitro to figure out the possible mechanisms. In conclusion, this research can offer a new potential way for stroke therapy.

miR-210作为公认的低氧标志性miRNA在低氧刺激后显著升高，而在局灶脑缺血损伤后，其表达水平也出现显著变化。研究证实miR-210参与了与脑缺血性损伤密切相关的线粒体能量代谢、细胞生存、细胞周期、DNA修复、血管生成等过程。因此我们设想对脑缺血损伤进行miR-210调控，有助于改善脑缺血预后，本研究拟明确miR-210对脑缺血损伤的调控作用及其在损伤后病理生理过程中的部分调节机制。在此基础上，制备骨髓间充质干细胞来源的miR-210 微粒，治疗缺血性脑损伤，该手段具有易于通过血脑屏障、载运稳定、靶向释放、实现网络调控靶基因的优势。同时我们通过体内脑缺血模型和体外细胞缺氧模型验证miR-210微粒治疗缺血性脑损伤的有效性、靶向性及机制，为卒中治疗提供新的思路和尝试。

MiR-210作为低氧标志性miRNA，在受到低氧刺激后在多种细胞中显著升高并参与调节了缺血后血管生成，而在脑缺血损伤模型中我们证实了miR-210与脑缺血损伤程度及预后存在相关性联系。我们的研究发现miR-210在缺血性脑梗死小鼠模型中存在内皮和血管靶向性作用机制，发现其受缺氧缺血刺激干预调节。同时我们发现miR-210调控了其下游内皮特异分泌的IGFBP3在炎性损伤和缺氧刺激后表达变化，进而参与调节了内皮保护和血管新生活动。因此，缺氧及缺血刺激诱导了miR-210调节其下游脑微血管内皮分泌的IGFBP3变化，参与了脑缺血损伤后的微血管新生。而通过外源性微粒可转运miR-210改变脑内miR-210及下游靶点表达水平进而调节损伤后血管生成和内皮细胞功能，为促进脑缺血损伤恢复提供了新的靶点和方向。