Systemic perinatal insults disrupt neurodevelopment

系统性围产期损伤会破坏神经发育

基本信息

批准号：
6871314
负责人：
SHENANDOAH ROBINSON
金额：
$ 14.1万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-15 至 2009-02-28
项目状态：
已结题

项目摘要

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.

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，致力于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，促进她发展成为一名独立科学家。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。该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，该研究计划涉及确定脑瘫、癫痫和系统性围产期损伤后认知延迟的发病机制。需要准确了解系统性围产期损伤如何改变神经发育，以指导干预措施的制定，以尽量减少神经功能缺陷。侮辱会导致与脑瘫相关的白质病变，以及导致认知迟缓和癫痫的神经元异常。观察到的神经病理变化模式表明，各种损伤会引起发育中大脑的破坏和反应的共同机制。我们假设损伤诱导的促炎细胞因子破坏围产期产生和成熟的神经谱系的发育，包括少突胶质细胞和 GABA 能中间神经元。我们已经描述了大鼠产前全身缺血模型，该模型诱导新生儿 WML，模仿与人类脑瘫相关的模型，以及类似于癫痫中发现的 GABA 能神经元损失。在目标 1 中，我们将分析人类死后组织和大鼠产前缺血模型中损伤引起的神经细胞损失。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，以及这种损失是否可逆。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引起的神经细胞损失，并使用细胞因子抑制剂来增强损伤后新生儿神经发育。这些研究将共同确定损伤如何影响少突胶质细胞和 GABA 能神经元的发育、这种损失是否可逆，以及促炎细胞因子是否介导这种损失。对围产期神经发育破坏机制的深入了解将带来新的干预措施，以增强新生儿的神经发育，并最大限度地减少神经缺陷。