Blood-brain barrier changes via hypoxia/re-oxygenation

描述（由申请人提供）：缺血相关病理（心脏骤停、卒中、窒息等）在美国，这是导致死亡和长期残疾的主要原因。然而，关于缺血事件如何诱导血脑屏障（BBB）的破坏和增加的渗透性知之甚少。虽然与中风和心脏骤停相关的缺氧已被报道导致BBB通透性增加，但缺氧损伤后再氧合对脑内皮细胞的影响仍不清楚，并且已知的仅围绕体外建模。该建议的假设是缺氧/复氧诱导连接蛋白和细胞骨架蛋白的表达和定位的显著改变，导致BBB通透性增加。 这一建议扩展了以前的工作，缺氧损伤血脑屏障的功能，生物化学和分子的变化，脑内皮细胞在缺氧/复氧过程中，在整个动物模型。BBB通透性的变化，细胞骨架I紧密连接蛋白的改变，以及这些蛋白的分布I定位将在此病理检查。这项研究的数据将证明细胞骨架框架和连接蛋白的改变如何与缺氧/复氧过程中发生的功能变化（即细胞旁通透性）相关。对病理过程中发生的细胞机制的深入了解将有助于开发用于治疗缺血和相关脑改变的替代治疗策略。

DESCRIPTION (provided by applicant): Ischemia associated pathologies (cardiac arrest, stroke, asphyxiation, etc.) significantly contribute to death and long-term disability in the United States. However, little is understood in regards to how the ischemic event induces a breakdown and increased permeability of the blood-brain barrier (BBB). Although hypoxia associated with stroke and cardiac arrest has been reported to cause increased BBB permeability, effects of re-oxygenation on brain endothelial cells following a hypoxic insult remains unclear, and what is known revolves solely around in vitro modeling. The hypothesis of this proposal is hypoxia / re-oxygenation induces significant alterations in the expression and localization of junctional and cytoskeletal proteins leading to increased BBB permeability. This proposal expands previous work on hypoxic insult to the BBB by focusing on functional, biochemical and molecular changes in brain endothelial cells during hypoxia / reoxygenation, in a whole animal model. Changes in BBB permeability, alterations in cytoskeletal I tight junction proteins, and distribution I localization of those proteins will be examined in this pathology. Data from this research will demonstrate how alterations in the cytoskeletal framework and junctional proteins are related to functional changes (i.e. paracellular permeability) that occur during hypoxia I re-oxygenation. The insight into the cellular mechanism, which occur over the time course of the pathology, will contribute to the development of alternative therapeutic strategies for the treatment of ischemia and associated brain alterations.