Oligodendrocyte Loss Following Early Ischemic Injury

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DESCRIPTION (provided by applicant) Fetal ischemic insult to the developing CNS results in irreversible and devastating functional consequences such as those observed in cerebral palsy. A hallmark of such early ischemic damage is a dramatic reduction in myelinated white matter. We propose to use a powerful model of fetal ischemia combined with biochemical and immunological tools that identify distinct stages in oligodendrocyte maturation to define the precise events affected by fetal ischemic insults. Normal oligodendrocyte development involves a number of crucial regulatory events, only some of which appear compromised by fetal ischemia. We hypothesize, based on preliminary data, that the loss of white matter after ischemic injury reflects changes in regulatory molecules that control the proliferation, migration and survival of oligodendrocyte precursors. In the first aim we will identify the specific stages at which oligodendrocyte lineage cells are lost following fetal ischemic insult and test the hypothesis that the insult alters the expression of growth factors required for oligodendrocyte development. In the second aim we will test the hypothesis that prenatal ischemic insult reduces the proliferation and migration of oligodendrocyte precursors. In the third aim we will quantify oligodendrocyte precursor cell death following ischemic insult and test the role of several different identified regulatory molecules in the induction of oligodendrocyte cell death. These studies utilize a model of fetal ischemia to identify the injury-susceptible events in oligodendrocyte maturation that eventually result in loss of white matter. Completion of this project will identify candidate molecules that will be useful for the development of novel therapeutic interventions for treating a common and devastating pediatric CNS problem.