Systemic perinatal insults disrupt neurodevelopment

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DESCRIPTION (provided by applicant): The candidate is an Assistant Professor in the Departments of Neurosurgery and Neuroscience at CWRU who is pursuing an academic career combining patient care with translational research. The KO8 award will foster her development into an independent scientist by providing support while the candidate seeks an R01. The candidate has independent dedicated laboratory space, an experienced mentor, and full institutional support. The candidate's clinical practice focuses on surgical treatment of children with cerebral palsy and epilepsy, and integrates well with the research plan, which involves defining the pathogenesis of cerebral palsy, epilepsy, and cognitive delay after systemic perinatal insults. A precise understanding of how systemic perinatal insults alter neural development is needed to guide development of interventions to minimize neurologic deficits. Insults cause both white matter lesions associated with cerebral palsy, and neuronal abnormalities that cause cognitive delay and epilepsy. The pattern of neuropathological changes observed suggests that various insults induce a common mechanism of disruption and response by the developing brain. We hypothesize that insult-induced pro-inflammatory cytokines disrupt development of neural lineages arising and maturing in the perinatal period including oligodendrocytes and GABAergic interneurons. We have characterized a rat prenatal systemic ischemia model that induces neonatal WML that mimic those associated with human cerebral palsy, and GABAergic neuronal loss similar to that found in epilepsy. In Aim 1 we will analyze insult-induced neural cell loss in human post-mortem tissue and a rat prenatal ischemia model. In Aim 2, we will determine whether insults alter signaling pathways that regulate developmental functions, what cell types mediate the loss, and whether the loss is reversible. In Aim 3, we will use biological assays and functional tests to determine whether pro-inflammatory cytokines mediate insult-induced neural cell loss, and use cytokine inhibitors to enhance post-insult neonatal neurodevelopment. Together, these studies will define how insults affect oligodendrocyte and GABAergic neuronal development, whether the loss is reversible, and whether pro-inflammatory cytokines mediate the loss. Insights into mechanisms underlying the disruption of perinatal neural development will lead to novel interventions to enhance neural development in neonates, and minimize neurologic deficits.