Blood-brain barrier changes via hypoxia/re-oxygenation

描述(申请人提供)：与缺血相关的病理(心脏骤停、中风、窒息等)在美国，这是导致死亡和长期残疾的重要原因。然而，关于缺血事件是如何导致血脑屏障(BBB)破裂和通透性增加的，人们知之甚少。尽管与中风和心脏骤停相关的低氧已被报道导致血脑屏障通透性增加，但低氧损伤后复氧对脑内皮细胞的影响仍不清楚，已知的仅限于体外建模。这一设想的假设是，缺氧/复氧导致连接蛋白和细胞骨架蛋白的表达和定位发生显着变化，导致血脑屏障通透性增加。 这一建议扩展了以前关于低氧对血脑屏障的损害的工作，通过在整个动物模型中关注低氧/复氧过程中脑内皮细胞的功能、生化和分子变化。血脑屏障通透性的变化，细胞骨架I紧密连接蛋白的变化，以及这些蛋白的分布和定位将在本病理学中进行研究。这项研究的数据将展示细胞骨架和连接蛋白的变化如何与缺氧和复氧过程中发生的功能变化(即细胞旁通透性)有关。对细胞机制的洞察，发生在病理的时间过程中，将有助于开发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.