Hypoxic-ischemic brain injury affects 150,000 infants per year, resulting in developmental disabilities including cognitive impairment and cerebral palsy. Though no therapies exist, cell replacement from the subventricular zone (SVZ), a source of neural stem cells (NSCs), holds exciting promise. In development, neuroblasts from the SVZ migrate to the olfactory bulbs and a separate lineage of glioblasts migrates throughout the forebrain. After middle cerebral artery occlusion in adult rats SVZ cells move toward the ischemic lesion, but their migratory response to neonatal hypoxia-ischemia (H/l) has not been defined. This proposal will examine the SVZ's response to H/l, specifically whether SVZ neuroblasts become redirected toward the lesion, whether SVZ glioblasts move into the forebrain in greater numbers, and whether SVZ cell fate becomes shifted towards neurons. Processes of neural cell migration and differentiation are inextricably tied; differentiated phenotypes emerge as migration ceases. While the neuroblast marker Doublecortin (Dcx) is necessary for embryonic cortical migration, it is unknown whether it is necessary for migration towards neonatal H/l lesions. The candidate proposes to test the following hypotheses in 3 Aims: 1) that SVZ neuroblasts and glioblasts redirect their migration toward brain areas injured by H/l; 2) that SVZ NSCs expand lineage restrictions following H/l; and 3) that Dcx is necessary for SVZ neuronal migration in response to H/l. She will employ the Rice-Vannucci model of in vivo H/l, neurosphere and slice cultures, retroviral tagging and lineage analysis, multiphoton time-lapse microscopy and RNA interference. Investigations will provide an important understanding of SVZ cell behavior in response to neonatal H/l and serve as a starting point for developing strategies to harness endogenous NSCs for repair. Furthermore, they will define the lineage relationships between SVZ neurons and glia. The candidate's long-term career goal is to develop an academic career in Neonatology with a basic research focus on neural stem cell responses to hypoxia-ischemia. The rich environment provided by her mentor Dr. Francis Szele, Assistant Professor of Pediatrics, by her co-mentor Dr. John Kessler, Professor and Chair of Neurology, and by Northwestern University Feinberg School of Medicine will provide the resources necessary to help her to achieve her objectives. ? ?
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