LncRNA-I14Rik靶向miR-143调节脑卒中血脑屏障损伤的作用及机制研究

Stroke is a common feature of acute cerebrovascular disease characterized by focal neurological deficit, which is the world's second most common cause of death. Mounting evidence demonstrated that blood-brain barrier (BBB) damage play a critical role in the progress of stroke. Our previous study have indicated that miR-143 was upregulated in the ipsilateral side induced by transient middle cerebral artery occlusion. Moreover, silencing miR-143 protected the integrity of BBB induced by stroke, suggesting that miR-143 may be a critical element in stroke-induced BBB damage with subsequent neuroinflammation. Although the role of miRNA in regulating gene transcription have extensively studied, the crossregulation between LncRNA and miRNA has attracted increasing interest. LncRNA array indicated that LncRNA-I14Rik was significantly downregulated in the ischemic core and over-expression of LncRNA-I14Rik protected the integrity of BBB in vitro induced by oxygen-glucose deprivation. Furthermore, there exists a site complementary to miR-143 in the LncRNA-I14Rik as predicted by bioinformatics, this is further confirmed by miR-143 pull down assay, suggesting that there is interaction between LncRNA-I14Rik and miR-143. Therefore, we hypothesized that LncRNA-I14Rik targeting miR-143 may be envisioned as new avenues for the development of potential therapeutic targets for BBB damage in stroke. Our current proposal is to examine whether LncRNA-I14Rik, as a competing endogenous RNA (ceRNA), compete with miR-43 then affect the regulation and function of target HECTD1. This proof of concept study will test the efficacy of over-expression of LncRNA-I14Rik as a therapeutic strategy for ameliorating the damage of BBB induced by stroke. This proposal is both novel and innovative in that the efficacy of LncRNA-I14Rik over-expression in abrogating the dysfunction of BBB can be of value for stroke-mediated neuroinflammation. Our study will understand the role of LncRNA-I14Rik in the BBB damage induced by stroke providing insight for opening up novel therapeutic avenues for neuroinflammation induced by stroke.

脑卒中是以局灶性神经功能缺失为特征的急性脑血管病，是全球第二大常见死因。血脑屏障（blood-brain barrier, BBB）损伤是脑卒中发生发展的重要始动因素之一。前期研究发现，脑卒中缺血区miR-143表达水平升高并参与脑卒中BBB损伤。二代测序发现脑卒中模型鼠LncRNA-I14Rik（I14Rik）显著下降，并且I14Rik过表达逆转氧糖剥夺引起的BBB通透性增加。I14Rik转录本存在与miR-143结合的位点，提示I14Rik有可能靶向miR-143而调节BBB损伤。因此，申请者提出“I14Rik靶向miR-143调节脑卒中BBB损伤”这一假设，探讨I14Rik与miR-143竞争结合下游靶基因-E3连接酶抑制素受体的可能机制，即竞争性内源RNA(ceRNA)机制，改善脑卒中BBB损伤。本项目研究成果将对治疗脑卒中BBB损伤提供新的视角和治疗策略。

脑卒中是以局灶性神经功能缺失为特征的急性脑血管病，是全球第二大常见死因。血脑屏障（blood-brain barrier, BBB）损伤是脑卒中发生发展的重要始动因素之一。本项目以“miR-143调节血脑屏障完整性及其调控机制”为主要研究内容，明确miR-143在血脑屏障损伤中的作用，更新了现有关于BBB损伤发生和治疗的理论，对临床治疗策略和治疗药物靶标的创新具有重要意义。此外，本项目还拓展研究内容至其他非编码RNA领域，证实其他非编码RNA在缺血性脑卒中中的作用，为治疗缺血性脑卒中提供新的视角和治疗策略。在该项目的资助下，申请人共发表论文17篇，包括Circulation，Molecular Psychiatry，Biological Psychiatry，Microbiome和Stroke等高影响力杂志。申请国内发明专利4项，其中1项已经授权，另3项已公开。申请人获得国家自然科学杰出青年科学基金项目资助，并荣获科技部中青年科技领军人才、江苏省双创团队（领军人才）和第十六届江苏省青年科技奖等荣誉。