Systemic perinatal insults disrupt neurodevelopment

描述（由申请人提供）：该候选人是CWRU神经外科和神经科学部门的助理教授，正在寻求将患者护理与转化研究相结合的学术生涯。KO8奖将在候选人寻求R01的过程中提供支持，帮助她成长为独立的科学家。候选人有独立的专用实验室空间，有经验丰富的导师和充分的机构支持。该候选人的临床实践侧重于脑瘫和癫痫患儿的外科治疗，与研究计划很好地结合，研究计划涉及脑瘫、癫痫和围产期全身损伤后认知延迟的发病机制。

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.