These studies are based upon the characterization by this lab of a number of different stress proteins in the brain and in cultured brain cells. One well characterized stress protein is the HSP70 heat shock protein which is hypothesized to protect against focal and global cerebral ischemia by decreasing protein denaturalization. Another group of potentially important proteins are the oxygen regulated proteins, hemeoxygenases 1 and 2, which are hypothesized to exacerbate reperfusion injury due to their potential to release iron, CO, and bilirubin. Also, the newly discovered hypoxia-inducible factor-1 will be studied because as a transcription factor, it may induce hypoxia responsive target genes, e.g., glycolytic enzymes and vascular endothelial growth factor. Approaches to these studies include the use of both focal and global cerebral ischemia models and a neonatal hypoxia model. Transgenic HSP70 over expressors and heme oxygenase knockout mice will be employed to test the positive or negative effects of these proteins. Molecular techniques will be utilized to determine both post-ischemic and hypoxia-induced preconditioned levels of specific RNAs and proteins. Histochemical determinations will be made to determine brain region specific gene expression so that expression can be correlated with selective neuronal vulnerability and cerebral blood flow. Ultimately, these studies may help characterize the role of stress genes in ischemic brain and should stimulate efforts at pharmacologically and genetically modulating the stress response to decrease ischemic neurodegeneration.
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