Stroke induces neural stem cells to differentiate into immature neuroblasts, migrate from the subventricular zone into the area of damage, and differentiate into neurons. These findings suggest that the adult brain has a limited process of neuronal regeneration after stroke. Neural stem cells depend on a biochemical niche that is linked to the vascular system and utilize vascular endothelial growth factor (VEGF) and erythropoietin (Epo) for neuronal differentiation. Together, VEGF and Epo are under the control of the hypoxia inducible transcription factor (Hif-1). Hif-1 is induced after focal ischemia and the Hif-1 target genes VEGF and Epo are increased near the area of injury after stroke. This data shows that the neural stem cells utilize the Hif system, and that Hif signaling is induced by stroke. These findings have lead to the hypothesis for my project: that HIF-1a, VEGF, and Epo are important for subventricular-derived neuroblast migration to areas of injury following a focal stroke. The specific aims for this project are to determine the colocalization of the Hif system with migrating neuroblasts after stroke. I will characterize the expression patterns of HIF1, VEGF, Epo and EpoR in association with migration of neuroblasts to peri-cortex. Focal ischemia will be induced with permanent distal MCA ligation. Animals will be sacrificed, and analyzed immunohistochemically for the pattern and of HIF-1, VEGF, Epo and EpoR. Hif-1, VEGF, Epo and EpoR staining will be performed with polysialic neural cell-adhesion molecule staining in confocal immunofluorescence to co-localize components of the Hif system with migrating neuroblasts.
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