Our hypothesis is that there is a complex, dynamic interaction between neurotrophic receptor and """"""""vascular"""""""" receptor signaling in neurons and endothelia in the CNS during postnatal development and it is disrupted during chronic sublethal hypoxia. During this grant period, using a variety of methodologies, we propose to: 1. Characterize the expression of neurotrophic (NT) receptors (BDNF receptors) and VEGF & angiopoietin receptors (VEGFR1 & 2, Tie2) on neurons and endothelia in the CNS (cortex) in vivo and in vitro in normoxic and hypoxic conditions. 2. Characterize the interactions and the signaling pathways involved following NT (trkB & p75NGF) and VEGF (VEGFR1 & R2) receptor engagement in neurons in vitro in normoxic and hypoxic conditions. Specifically, we will determine: the effects of VEGFR signaling upon NT receptor expression and signaling in cerebral neurons; the effects of NT signaling upon VEGF receptor expression and signaling in cerebral neurons; and the effects of sequential NT and VEGF (and VEGF and NT) receptor engagement upon neuronal proliferation, survival and differentiation. 3. Characterize the interactions and the signaling pathways involved following NT (trkB & p75NGF) and VEGF (VEGFR1 & R2) receptor engagement in cerebral endothelial cells in vitro in normoxic and hypoxic conditions. Specifically, we will determine; the effects of VEGFR signaling upon NT receptor (trkB & p75NGF) and ligand (BDNF) expression in cerebral microvascular endothelial cells; the effects of NT signaling (via BDNF) upon VEGF receptor expression and signaling in cerebral microvascular endothelial cells; and the effects of sequential NT and VEGF (and VEGF and NT) receptor engagement upon endothelial proliferation, survival and differentiation. 4. Determine NT and VE--GF receptor and ligand expression patterns and interactions in cocultures of neurons & cerebral microvascular endothelial (RBE4) cells; RBE4 cells & astrocytes; and neurons, RBE4 cells and astrocytes in vitro in normoxic and hypoxic conditions. 5. Investigate and characterize selected novel genes identified in our core facility by cDNA array analyses that are modulated during chronic hypoxia and pertinent to Aims 1 - 4. The experiments proposed in this grant application have as their goal the elucidation of the complex, dynamic interactions between neurotrophic receptor and """"""""vascular"""""""" receptor signaling in neurons and endothelia in the CNS during postnatal development and their disruptions during chronic sublethal hypoxia. Knowledge accrued during the next grant period will facilitate the development of new and novel rational therapeutic approaches and agents which will be more specific and selective in their modulation of these cell types during the critical period of postnatal brain development in the premature newborn.
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