Systemic perinatal insults disrupt neurodevelopment

描述（由申请人提供）：候选人是CWRU神经外科和神经科学系的助理教授，他正在追求将患者护理与转化研究相结合的学术生涯。KO8奖将通过在候选人寻求R01时提供支持来促进她成为独立科学家的发展。候选人拥有独立的专用实验室空间，经验丰富的导师和全面的机构支持。候选人的临床实践侧重于脑瘫和癫痫儿童的手术治疗，并与研究计划很好地结合，其中包括定义脑瘫，癫痫和系统性围产期损伤后认知延迟的发病机制。 需要准确了解围产期全身性损伤如何改变神经发育，以指导干预措施的发展，以尽量减少神经功能缺损。侮辱既会导致与脑瘫相关的白色病变，也会导致导致认知延迟和癫痫的神经元异常。观察到的神经病理学变化的模式表明，各种侮辱诱导一个共同的机制，中断和发育中的大脑的反应。我们推测，在围产期，包括少突胶质细胞和GABA能中间神经元在内的神经谱系的产生和成熟过程中，胰岛素诱导的促炎细胞因子会破坏其发育。我们的特点是大鼠产前全身缺血模型，诱导新生儿WML，模仿那些与人类脑瘫，GABA能神经元的损失类似的癫痫。在目标1中，我们将分析人死后组织和大鼠产前缺血模型中的损伤诱导的神经细胞损失。在目标2中，我们将确定损伤是否会改变调节发育功能的信号通路、哪些细胞类型介导这种损失以及这种损失是否是可逆的。在目标3中，我们将使用生物测定和功能测试来确定促炎细胞因子是否介导损伤诱导的神经细胞损失，并使用细胞因子抑制剂来增强损伤后新生儿神经发育。总之，这些研究将确定损伤如何影响少突胶质细胞和GABA能神经元的发育，这种损失是否是可逆的，以及促炎细胞因子是否介导了这种损失。深入了解围产期神经发育中断的机制将导致新的干预措施，以提高新生儿的神经发育，并尽量减少神经功能缺损。

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.