Systemic perinatal insults disrupt neurodevelopment

系统性围产期损伤会破坏神经发育

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6871314
• 关键词: biological signal transduction; cell population study; cell type; cerebral palsy; clinical research; cognition disorders; cytokine; developmental disease /disorder; developmental neurobiology; disease /disorder etiology; embryo /fetus hypoxia; epilepsy; gamma aminobutyrate; gene expression; human fetus tissue; infant human (0-1 year); inflammation; interneurons; laboratory rat; metallothionein; neural degeneration; neurogenesis; neuropathology; newborn animals; oligodendroglia; pathologic process; patient oriented research; perinatal

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.

应聘者描述(由申请人提供)：应聘者是CWRU神经外科和神经科学系的助理教授，正在追求将患者护理与翻译研究相结合的学术生涯。KO8奖将通过在候选人寻求R01的同时提供支持，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。候选人的临床实践专注于脑瘫和癫痫儿童的手术治疗，并与研究计划很好地结合在一起，研究计划涉及定义脑瘫、癫痫和围产期系统性侮辱后认知延迟的发病机制。 需要对系统性围产期侮辱如何改变神经发育的准确理解，以指导干预措施的发展，以最大限度地减少神经缺陷。侮辱既会导致脑瘫相关的脑白质损伤，也会导致认知延迟和癫痫的神经元异常。观察到的神经病理变化模式表明，各种侮辱都会导致发育中的大脑产生一种共同的干扰和反应机制。我们假设，侮辱诱导的促炎细胞因子破坏了围产期产生和成熟的神经系的发育，包括少突胶质细胞和GABA能中间神经元。我们已经确定了一种大鼠产前全身缺血模型的特征，该模型可以诱导出与人类脑瘫相关的新生儿WML，以及与癫痫中发现的类似的GABA能神经元丢失。在目标1中，我们将分析创伤诱导的人死后组织和大鼠产前缺血模型中的神经细胞丢失。在目标2中，我们将确定侮辱是否改变了调节发育功能的信号通路，什么细胞类型介导了这种丧失，以及这种丧失是否可逆。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了侮辱诱导的神经细胞丢失，并使用细胞因子抑制剂来促进侮辱后新生儿的神经发育。总之，这些研究将确定侮辱如何影响少突胶质细胞和GABA能神经元的发育，这种丧失是否可逆，以及促炎细胞因子是否介导了这种丧失。对围产期神经发育中断的潜在机制的洞察将导致新的干预措施，以促进新生儿的神经发育，并将神经缺陷降至最低。