The role of VEGF in neonatal rat brain after perinatal hypoxic-ischemic damage

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DESCRIPTION (provided by applicant): Perinatal hypoxia-ischemia (H/l) is strongly associated with cerebral palsy and a wide spectrum of other neurological deficits in children. While some researchers focus their attention on the use of exogenous stem cells for repair, our lab is evaluating the regenerative potential of the resident precursors of the subventricular zone (SVZ). Two key processes required to repair damaged organs are to amplify the number of precursors and to direct their differentiation towards the cell types that need to be replaced. Our most recent preliminary data indicate: 1) although the SVZ expands in size after H/l injury, there is a shift in the production of astrocytes and oligodendrocytes; 2) vascular endothelial growth factor (VEGF), a key mediator of tissue repair after ischemia, is rapidly induced after H/l; and 3) VEGF increases the specification of astrocytes from bipotential glial progenitors in vitro. While VEGF has been studied in adult stroke models, there are no known studies examining VEGF proteins after perinatal brain damage. Our hypothesis is that VEGF isoforms cause an aberrant shift in the proliferation and differentiation of SVZ progenitors towards astrocytic phenotypes instead of a more appropriate oligodendrocyte lineage after H/l injury. The following specific aims are proposed to test these hypotheses: Specific Aim 1: To characterize the expression profiles spatially and temporally in the SVZ of VEGFs A, B and C and the two main receptors, Flt-1 and Flk-1 after perinatal H/l. Specific Aim 2: To determine the effect of exogenous VEGF-A after in vitro H/l on the proliferation and differentiation of SVZ-derived bipotential glial progenitors. All experiments will be performed on rat pups using an established animal model for H/l. Importantly, these translational studies investigate a clinically important human condition. This project will enhance our understanding of stem cell proliferation and differentiation in the neonatal brain after injury. These studies will elucidate the role of VEGF on neural progenitor cell proliferation and differentiation in the context of perinatal brain injury. PUBLIC HEALTH RELEVANCE: Brain injury in children and infants is a serious public health issue that results in long term cognitive, motor and emotional handicaps. The goal of this research is to better understand how the brain repairs itself after H/l. Our work will also be relevant to other injuries and diseases of the CNS, such as stroke and traumatic brain injury where stem cell therapies will be implemented.