H19/miR-18a/VEGF轴以外泌体为载体诱导缺血性脑卒中血脑屏障破坏的机制研究

Long non-coding RNA H19 (lncRNA H19) is transcribed from H19 gene, our previous studies have revealed that lncRNA H19 could lead to the onset of cerebral ischemic stroke through activating neuronal autophagy or inducing microglial polarization. Our latest research found that lncRNA H19 participated in the process of blood brain barrier disruption involved in cerebral ischemic stroke. LncRNA H19 does not express or could not regulate the process of blood brain barrier disruption in astrocyte or microglia-- the core members of blood brain barrier. While the mimic ischemic stroke treatment could upregulate the expression of lncRNA H19 in the exosomes secreted by neuron. The upregulation of lncRNA H19 could inhibit the expression of miR-18a in microglia, and VEGF, the target of miR-18a could help to induce blood brain barrier interruption in the acute phase of ischemic stroke. Therefore, we suppose that lncRNA H19 is transferred from neuron to astrocyte through exosome, then it activates H19/miR-18a/VEGF axis to induce the disruption of blood brain barrier. The aim of this project is to validate the up-mentioned hypothesis to apply new target for the treatment of cerebral ischemic stroke.

长链非编码RNA H19（lncRNA H19）由H19基因转录而来，我们前期研究揭示lncRNA H19可诱导缺血性脑卒中发病，并于最近发现lncRNA H19参与诱导血脑屏障破坏，氧糖剥夺上调神经元外泌体lncRNA H19水平，而血脑屏障核心成员星形胶质细胞及内皮细胞不表达或自身表达的lncRNA H19不参与破坏血脑屏障。由此推测神经元以外泌体为载体将lncRNA H19运输至星形胶质细胞致其释放某些物质作用于内皮细胞诱导血脑屏障破坏。进一步研究发现上调星形胶质细胞中lncRNA H19表达可抑制其miR-18a水平，而miR-18a的靶蛋白VEGF是缺血性脑卒中急性期诱导内皮细胞损伤的关键蛋白。综上lncRNA H19以外泌体为载体由神经元运输至星形胶质细胞，激活H19/miR-18a/VEGF轴损伤内皮细胞诱导血脑屏障破坏。本项目旨在验证以上假说，为缺血性脑卒中治疗开辟新思路。

本项目从微观视角入手，从基因层面出发，以长链非编码RNA为突破口，展开了有关缺血性脑卒中发病机制的系列研究，在顺利完成项目既定研究目标的基础上，积极开展后续研究，成果颇丰。长链非编码RNA H19（lncRNA H19）由H19基因转录而来，我们前期研究揭示lncRNA H19可诱导缺血性脑卒中发病，并于最近发现lncRNA H19参与诱导血脑屏障破坏，氧糖剥夺上调神经元外泌体lncRNA H19水平，而血脑屏障核心成员星形胶质细胞及内皮细胞不表达或自身表达的lncRNA H19不参与破坏血脑屏障。由此推测神经元以外泌体为载体将lncRNA H19运输至星形胶质细胞致其释放某些物质作用于内皮细胞诱导血脑屏障破坏。进一步研究发现上调星形胶质细胞中lncRNA H19表达可抑制其miRNA-18a水平，而miRNA-18a靶蛋白VEGF是缺血性脑卒中急性期诱导内皮细胞损伤的关键蛋白。综上，lncRNA H19以外泌体为载体由神经元运输至星形胶质细胞，激活H19/miRNA-18a/VEGF轴损伤内皮细胞诱导血脑屏障破坏。本项目在此基础上，进一步证实了lncRNA H19通过激活lncRNA H19／p53/Notch轴抑制神经血管新生，lncRNA H19参与调控缺血性脑卒中患者阿司匹林抵抗，lncRNA H19以外泌体为载体，通过H19/let-7a/IGF1R轴诱导缺血性脑卒中的发病。本项目为缺血性脑卒中的治疗提供了新的靶点，开辟了新的思路。