Our data support the concept of variable responses to brain injury in the preterm infant population. We hypothesize that survival and recovery from such injuries is due in part to a coupled neurogenic/vasculoangio-genic response in the neurovascular niche areas of the brain (including the subventricular zone - SVZ) and that HIF-la induced BDNF upregulation in the vascular system is required for endothelial cell survival, proliferation and vasculogenesis and neural progenitor cell survival, proliferation and behavioral recovery. A systematic in vivo and in vitro investigation of neural stem/progenitor cells (NSCs) and their associated microvasculature in the neurovascular niche areas utilizing a broad range of techniques is warranted in order to develop rational therapeutic approaches that optimize recovery. Using murine models of chronic sublethal hypoxia we determined that the survival and recovery of this insult (which mimics the chronic sublethal hypoxia of the preterm infant population) is variable and depends in part upon the responsiveness of the NSCs and microvascular endothelial cells (ECs) in the neurogenic zones. We hypothesize that the upregulation of BDNF in the vascular system may be crucial for the beneficial effect of sensorimoror enrichment in these processes. This project will define the extent to which the HIF-la in the vascular endothelium is responsible for endothelial cell survival, proliferation and vasculogenesis and contributes to neural progenitor cell survival, proliferation and behavioral recovery. This will be tested by using endothelial HIF-la deficient mice that will be exposed to hypoxia followed by standard or enriched environments. Survival, proliferation differentiation, and apoptosis of the ECs and NSCs resident in the SVZ will be investigated in vivo and in vitro using 2- &3-dimensional co-cultures. The effects of NPC TrkB paracrine signaling on EC behavior will be assessed in both in vivo and in vitro assays as will white matter angiogenesis and vascular density in hEGFR over-expressing mice and HIF-la modulation of UCP2 expression, function and mitochondrion number in collaboration with the other projects in this P01.
Premature infants are at substantial risk to develop multiple neurodevelopmental handicaps due to chronic lack of adequate oxygenation. This project will elucidate the underlying responses to this lack of oxygen in brain cells and provide the basis for developing therapeutic responses, abrogating the effects of this lack of oxygenation during this critical period of brain development.
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