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 migrate 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 grant 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 timelapse 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 achieve her objectives.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS053529-05
Application #
7755023
Study Section
NST-2 Subcommittee (NST)
Program Officer
Owens, David F
Project Start
2006-01-01
Project End
2011-03-31
Budget Start
2010-01-01
Budget End
2011-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$145,374
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
074438755
City
Chicago
State
IL
Country
United States
Zip Code
60611
Birch, Derin; Britt, Blair C; Dukes, Silena C et al. (2014) MicroRNAs participate in the murine oligodendroglial response to perinatal hypoxia-ischemia. Pediatr Res 76:334-40
Dizon, Maria L V; Maa, Tensing; Kessler, John A (2011) The bone morphogenetic protein antagonist noggin protects white matter after perinatal hypoxia-ischemia. Neurobiol Dis 42:318-26
Dizon, Maria; Szele, Francis; Kessler, John A (2010) Hypoxia-ischemia induces an endogenous reparative response by local neural progenitors in the postnatal mouse telencephalon. Dev Neurosci 32:173-83