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.
| Witt, Ken A; Mark, Karen S; Sandoval, Karin E et al. (2008) Reoxygenation stress on blood-brain barrier paracellular permeability and edema in the rat. Microvasc Res 75:91-6 |
| Witt, Ken A; Mark, Karen S; Huber, Jason et al. (2005) Hypoxia-inducible factor and nuclear factor kappa-B activation in blood-brain barrier endothelium under hypoxic/reoxygenation stress. J Neurochem 92:203-14 |
| Witt, Ken A; Mark, Karen S; Hom, Sharon et al. (2003) Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol 285:H2820-31 |
