骨髓间充质干细胞在缺血性卒中后抑制水通道蛋白4保护血脑屏障完整性的机制研究

项目名称： 骨髓间充质干细胞在缺血性卒中后抑制水通道蛋白4保护血脑屏障完整性的机制研究

项目编号： No.81471178

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨国源

作者单位： 上海交通大学

项目金额： 85万元

中文摘要： 水通道蛋白4（AQP4）在维持血脑屏障完整性中起重要作用。缺血性卒中后，局部炎症可引起星形细胞终足AQP4表达增高，导致血脑屏障破坏，引发脑水肿，是造成继发性脑损伤的重要原因之一。我们前期工作和国内外相关研究证明骨髓间充质干细胞（MSCs）能有效抑制炎症反应，减轻脑缺血引起的组织损伤，促进神经功能恢复，提示其在治疗缺血性卒中中有很好的应用前景。然而，MSCs是通过什么途径影响血脑屏障通透性仍不清楚。本课题拟通过小鼠大脑中动脉栓塞模型和星形细胞/MSCs共培养模型，应用活体分子影像等先进技术，探索：1）MSCs治疗是否能够抑制脑缺血诱导的局部炎症反应，从而减轻血脑屏障破坏和脑水肿；2）MSCs治疗是否通过抑制缺血诱导的星形细胞AQP4上调，从而减轻血脑屏障破坏；3）MSCs是通过什么途径调节星形细胞AQP4的表达。我们的研究结果将为减轻缺血后局部炎症引起的血脑屏障破坏提供新的治疗靶点。

中文关键词： 缺血性脑卒中；脑水肿；血脑屏障；星形胶质细胞；水通道蛋白4

英文摘要： Aquaporin-4 plays a critical role in the maintenance of its integrity. Focal inflammatory response induced astrocyte-specific aquaporin-4 overexpression after ischemic stroke exacerbates blood brain barrier destruction, which results in brain edema. This process is one of the crucial causes for secondary brain injury after ischemic stroke. Our previous studies and related research demonstrated that mesenchymal stem cells effectively inhibited inflammatory response redcued brain injury and promoted neurological functional recovery after ischemic stroke, suggesting a great potential in the treatment of ischemic stroke. However, the mechanism of how mesenchymal stem cells affect blood brain barrier permeability remains unknown. We intend to use a mouse middle cerebral artery occlusion model in vivo, and an astrocytes/mesenchymal stem cells co-culture model in vitro, and apply novel techniques in molecular imaging in vivo to explore: 1) whether mesenchymal stem cells inhibit local inflammatory response after ischemic stroke and in turn decrease blood brain barrier disruption and brain edema; 2) whether mesenchymal stem cells inhibit ischemic stroke-induced aquaporin-4 up-regulation, consequently, attenuating blood brain barrier disruption; 3) the mechanism by which mesenchymal stem cells regulate astrocyte-specific aquaporin-4 expression. Our results may provide a novel therapeutic target for blood brain barrier disruption caused by ischemic stroke.

英文关键词： ischemic stroke;brain edema;blood brain barrier;astrocyte;Aquaporin-4