SNHG12/miR-181b/PTEN信号轴在缺血性脑卒中后血管新生中的作用及其调控机制研究

Ischemic stroke greatly threatens human health due to the high morbidity, disability and mortality. To clarify the regulatory mechanism of angiogenesis following stroke and to find effective measures to promote angiogenesis is expected to change the current difficulties in the treatment of stroke. In our preliminary research, we found that the expression of a long noncoding RNA (SNHG12) was significantly increased in the ischemic brain tissues after MCAO in rats and was negatively correlated with the microvessel density. At the cellular level, SNHG12 inhibited angiogenesis through upregulating PTEN expression and downregulating the phosphorylation of Akt, suggesting that SNHG12 may inhibit angiogenesis after ischemic stroke, but there are still many questions needed to be clarified. This project aims to further determine the role of SNHG12 in angiogenesis following ischemic stroke by molecular, cellular and animal experimental studies and to investigate the regulatory mechanism of SNHG12/miR-181B/PTEN signal axis in this process. The implementation of this project will be useful to clarify the regulatory relationship between SNHG12, miR-181B and PTEN, and further reveal the molecular mechanism of angiogenesis in ischemic stroke, and provide new ideas for effectively inducing post-ischemic angiogenesis, improving blood supply, promoting neurovascular remodeling and functional recovery.

缺血性脑卒中因发病率、致残率、死亡率高而严重危害人类健康。阐明卒中后血管新生分子调控机制，并寻找有效措施促进血管新生有望改变目前脑卒中的治疗困境。课题组前期研究发现长链非编码RNA(SNHG12)在大鼠MCAO后缺血脑组织中表达显著增高，且其表达水平与微血管密度呈负相关；SNHG12在细胞水平通过上调PTEN表达，下调p-Akt表达抑制血管形成，提示SNHG12可能抑制缺血性脑卒中后血管新生，但仍有许多疑问有待阐明。本项目拟通过分子、细胞及动物多层面实验研究进一步明确SNHG12在缺血性脑卒中后血管新生中的作用，并探讨SNHG12/miR-181b/PTEN信号轴在该过程中的调控机制。本项目实施将有助于阐明SNHG12、miR-181b和PTEN之间的调控关系，进一步揭示缺血性脑卒中血管新生的分子机制，为有效诱导缺血区血管新生，改善局部血供，促进神经血管结构重塑和功能修复提供新的思路。

缺血性脑卒中因发病率、致残率、死亡率高而严重危害人类健康，阐明卒中后血管新生分子调控机制，并寻找有效措施促进血管新生有望改变目前脑卒中的治疗困境。本课题分别从体外和体内验证了SNHG12/miR-181b/PTEN信号轴在缺血性脑卒中后血管生成中的重要作用。体外研究发现，通过敲减SNHG12和过表达miR-181b，能够抑制HBMVEC细胞OGD后PTEN表达，激活Akt通路，调控血管生成相关因子VEGF、ES，和凋亡蛋白Cleaved Caspase-3、Cleaved Caspase-9、BCL2的表达，从而提高HBMVEC细胞OGD后增殖、迁移和侵袭能力，以及体外血管生成的能力，并抑制细胞凋亡；体内研究发现，miR-181b过表达能够显著减小大鼠局灶性脑缺血后脑梗塞体积，提高动物神经功能缺损评分，并明显增加脑缺血后新生血管密度。以上结果为进一步研究缺血性脑卒中的发生机制及寻找新的治疗靶点提供了实验依据。