Vascular endothelial growth factor (VEGF or VEGF-A) is a hypoxia-inducible secreted protein that interacts with receptor tyrosine kinases on endothelial cells to promote angiogenesis. Recent evidence indicates that VEGF may also act directly on neurons to produce neurotrophic and neuroprotective effects, and on neuronal precursor cells in the adult brain to stimulate neurogenesis -- the process through which precursor cells differentiate towards a mature neuronal phenotype. The broad, overall objective of this work is to understand how VEGF affects neurons and their cellular precursors, and to identify possible therapeutic roles for VEGF in stroke and other neurological disorders. The hypothesis underlying this proposal is that VEGF acts directly on (A) cerebral neurons to protect them from hypoxia, ischemia and related insults and (B) neuronal precursors to promote neurogenesis.
The Specific Aims are to: (1) define the receptors and signal-transduction pathways through which VEGF protects cortical neurons from simulated ischemia and related insults in vitro, (2) investigate the mechanism by which VEGF protects neurons from focal cerebral ischemia in vivo, (3) determine the mechanism by which VEGF stimulates neurogenesis in cerebral cortical cultures in vitro, and (4) characterize the neurogenesis-promoting effect of VEGF in vivo with respect to which neuroproliferative zones are affected, which VEGF receptors are involved, whether the effect is produced by stimulating cell division or inhibiting cell death, and the migratory and functional fates of the target cells.
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