Mechanisms of Excitotoxic Injury to Oligodendrocytes

少突胶质细胞兴奋性毒性损伤的机制

• 批准号: 7006505
• 负责人: Frances E Jensen
• 金额: $ 30.85万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006505
• 关键词: AMPA receptors; NMDA receptors; astrocytes; biological signal transduction; brain injury; calcium flux; calcium indicator; cerebral ischemia /hypoxia; disease /disorder etiology; disease /disorder prevention /control; electrophysiology; free radical oxygen; human fetus tissue; laboratory rat; laser capture microdissection; membrane potentials; microglia; mitochondrial membrane; neurons; neuropathology; neurotoxicology; oligodendroglia; postmortem; protein structure function; receptor expression; tissue /cell culture; tissue resource /registry; white matter

Periventricular leukomalacia (PVL) occurs in preterm infants suffering cerebral hypoxia/ischemia and/or prior exposure to maternal-fetal infection, both of which can involve excitotoxic preoligodendrocyte (preOL) injury. A central hypothesis in this Project is that a major factor in PVL is the induction of glutamate receptor (GluR)-mediated excitotoxicity in cells intrinsic to white matter (WM). We further hypothesize that the developmental status of GluRs increases susceptibility of the WM to excitotoxic injury. Our in vitro and in vivo models of excitotoxic injury demonstrated that premyelinating OLs (preOLs) are selectively vulnerable to excitotoxicity and hypoxic/ischemic injury at least in part due to a developmental overexpression of calcium (Ca2+)-permeable alpha amino-3-hydroxy-5-methyl-4-isox-azole propionate (AMPA) and kainate (KA) ionotropic GluRs. We have shown that these GluRs are similarly overexpressed on OLs in developing human WM during the developmental window of vulnerability to PVL (23-36 gestational weeks). Our pharmacologic studies in vivo and in vitro demonstrate that preOL excitotoxicity can be attenuated by Ca2+-permeable AMPA/KA receptor antagonists. We have recently extended our studies to address the role of GluRs on preOLs in the clinically relevant setting of recurrent episodes of hypoxia/ischemia, and show that subthreshold, sublethal excitotoxic injury sensitizes preOLs to injury, and that this phenomenon is AMPA/KA receptor-dependent. In the present proposal, we will characterize in-depth the developmental expression of GluRs in normal human WM and determine whether expression is altered following PVL (Aim 1). We will determine alterations in GluR function, expression and signaling following lethal OGD and sublethal OGD in preOLs in vitro (Aim 2). In parallel, we will determine alterations in GluR function and expression following lethal hypoxic/ischemic injury and sublethal hypoxia in vivo (Aim 3). Finally, we aim to characterize expression of GluRs on other cell types in white matter during the window of vulnerability to hypoxic/ischemic white matter injury, and to evaluate GluR alterations in these cells following lethal hypoxia/ischemia or sublethal hypoxia in vivo (Aim4). Throughout the proposal, we examine mechanism of action and efficacy of therapeutic strategies targeting GluRs. The overall goal of this project is to gain improved understanding of the role of GluRs in PVL in order to design new age-specific therapies.

脑室脑膜白血病（PVL）发生在患有脑缺氧/缺血性缺血的早产儿和/或事先暴露于产妇感染中，这两种感染都可能涉及兴奋性氧化前腺胶质细胞（PEROL）损伤。该项目中的一个中心假设是，PVL的主要因素是诱导白质（WM）固有细胞中谷氨酸受体（GLUR）介导的兴奋性毒素。我们进一步假设，gl的发育状况增加了WM对兴奋性毒性损伤的敏感性。我们的体外和体内兴奋性毒性损伤模型表明，前髓的OLS（preols）有选择地容易受到兴奋性和兴奋性毒性的影响 低氧/缺血性损伤至少部分是由于钙（Ca2+）的发育过表达 - 可渗透的α氨基-3-羟基-5-甲基-4-甲基-4-异唑 - 丙酸酯（AMPA）和Kainate（KA）（KA）离子型胶质。我们已经表明，在PVL脆弱性的发展窗口中，在开发人类WM的OL中，这些gl虫（23-36胎周）也相似地过表达。我们在体内和体外的药理学研究表明，Ca2+可渗透的AMPA/KA受体拮抗剂可以减弱pre-Ol兴奋性。最近，我们扩展了研究，以解决gl的作用在临床相关的低氧/缺血性发作的临床相关环境中，并表明亚阈值，亚致死性兴奋性损伤使preols对损伤敏感，并且这种现象是AMPA/KA受体依赖性的。在本提案中，我们将深入介绍正常人WM中胶的发育表达，并确定PVL后是否改变了表达（AIM 1）。我们将在体外preols中致命的OGD和全脂OGD后确定Glur功能，表达和信号传导的改变（AIM 2）。同时，我们将确定在体内致命性低/缺血性损伤和余生性缺氧后GLUR功能和表达的改变（AIM 3）。最后，我们旨在表征在缺氧/缺血性白质损伤的窗口期间，在白质中其他细胞类型的表达表达，并在体内致死性低氧/缺血或余生性低氧后这些细胞的GLUR改变（AIM4）。在整个提案中，我们研究了针对胶卷的治疗策略的作用机理和功效。该项目的总体目标是提高人们对gl脂在PVL中的作用的了解，以设计新的年龄特异性疗法。