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。

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.