Hypoxia/Reoxygenation Effects on the Blood-brain Barrier

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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.