Hypoxia/Reoxygenation Effects on the Blood-brain Barrier

描述(由申请人提供)： 在美国，中风是导致死亡和长期残疾的主要原因 状态，然而关于缺血事件如何诱导 血脑屏障(BBB)破裂和通透性增加。虽然 据报道，与中风相关的低氧会导致血脑屏障升高。 通透性，复氧对脑内皮细胞的影响 缺氧性侮辱仍不清楚。这一建议的假设是Hvpoia 导致连接蛋白的表达和定位发生显著变化 和细胞骨架蛋白导致血脑屏障通透性和Tbese增加 在复氧过程中，效果会降低。 这项建议扩展了以前的低氧侮辱血脑屏障的工作，通过专注于 脑微血管内皮细胞功能和生化改变的研究 细胞在缺氧和复氧过程中。血脑屏障通透性变化， 细胞结构的改变(即，细胞骨架和 连接蛋白与磷酸化状态的变化/定位 模式将使用体外血脑屏障模型进行检验，如下 低氧/复氧治疗。总而言之，来自该项目的数据将 展示细胞骨架和连接处的改变 蛋白质与功能变化有关(例如，细胞旁增加 通透性)，发生在缺血期和复氧期 卒中。

DESCRIPTION (provided by applicant): Stroke is the leading cause of death and long-term disability in the United States, yet little is understood regarding how an ischemic event induces a breakdown and increased permeability of the blood-brain barrier (BBB). Although hypoxia associated with stroke has been reported to cause increased BBB permeability, effects of re-oxygenation on brain endothelial cells following a hypoxic insult remain unclear. Tbe hYpothesis of this proposal is that hvpoxia induces significant alterations in expression and localization of junctional and cYtoskeletal proteins leading to increased BBB perrneability and tbese effects are reduced during re-oxygenation. This proposal expands on previous work of hypoxic insult to the BBB by focusing on functional and biochemical alterations in brain microvessel endothelial cells during hypoxia and re-oxygenation. Changes in BBB permeability, alterations in cytoarchitecture (i.e., expression of cytoskeletal and junctional proteinsl, and changes in phosphorylation states/ localization patterns will be examined using an in vitro BBB model following hypoxia/re-oxygenation treatment. Together, data from this project will demonstrate how alterations in the cytoskeletal framework and junctional proteins are related to functional changes (i.e., increased paracellular permeability) that occur during hypoxia and re-oxygenation phases of ischemic stroke.