Glutamate Receptors in Hypoxic-ischemic Injury to Developing Oligodendrocytes

谷氨酸受体在发育中少突胶质细胞缺氧缺血性损伤中的作用

• 批准号: 7463517
• 负责人: Wenbin Deng
• 金额: $ 27.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463517
• 关键词: Acids; Adverse effects; Affect; Age; Agonist; Animal Model; Attenuated; Behavioral; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcineurin; Cell Death; Cell surface; Cells; Cerebral Palsy; Cerebral cortex; Cerebrum; Characteristics; Child Care; Data; Development; Disease; Drug Delivery Systems; Event; Gene Mutation; Gene Transfer; Glutamate Receptor; Goals; Hand; Human; Hypoxia; In Situ; In Vitro; Infant hypoxia; Injury; Ischemic-Hypoxic Encephalopathy; Knowledge; Laboratories; Mediating; Metabotropic Glutamate Receptors; Modeling; Molecular; N-Methylaspartate; Neurologic; Oligodendroglia; Outcome; Oxidative Stress; Pathway interactions; Pattern; Periventricular Leukomalacia; Permeability; Phosphorylation; Play; Predisposition; Premature Infant; Prevention strategy; Protein Kinase C; Proto-Oncogene Proteins c-akt; Public Health; Rattus; Receptor Signaling; Role; Signal Transduction; Signaling Molecule; Therapeutic; Toxic effect; Virus; age related; attenuation; base; citrate carrier; excitotoxicity; in vivo; insight; kainate; neuron loss; neurotransmission; novel; novel therapeutics; prevent; receptor; receptor expression; research study; tool; white matter; white matter injury

DESCRIPTION (provided by applicant): Hypoxic-ischemic injury to the developing brain leads to devastating neurological consequences. Strikingly, the pattern of hypoxic-ischemic brain injury is highly age-dependent. In term infants, hypoxia-ischemia predominantly affects cerebral cortex with characteristic neuronal loss. However, in premature infants, hypoxia- ischemia selectively affects cerebral white matter with prominent injury to the developing oligodendrocyte (OL), a disorder termed periventricular leukomalacia (PVL). The developing OL (pre-myelinating OL, termed "preOL") is highly vulnerable to hypoxic-ischemic injury and is the major cellular substrate of PVL. We have shown that glutamate receptor (GluR) expression is developmentally regulated on OLs in vivo and in vitro, and that ionotropic GluRs (iGluRs) mediate hypoxic-ischemic injury to preOLs, but metabotropic GluRs (mGluRs) can modulate this injury. However, the role of specific iGluRs and mGluRs in hypoxic-ischemic preOL injury and the signaling mechanisms remain largely unknown. The central hypothesis of the proposal is that Ca2+-permeable iGluRs mediate hypoxic-ischemic preOL injury and that group 1 mGluRs can modulate this injury, entailing the molecular interplay between iGluRs and mGluRs and the integration of distinct post-receptor signaling events. We will focus on determining the mechanisms of the crosstalk between iGluRs and mGluRs in preOL injury. The goal of this project is to provide new insights into the age-specific mechanisms of hypoxic-ischemic preOL injury, and to determine potential age-specific therapeutic strategies for treating preOL injury that underlies cerebral white matter disorders. Aim 1 of this proposal is to determine the sequence of alterations of iGluR function and signaling in preOL excitotoxicity, with the aim to identify specific therapeutically accessible targets. Aim 2 will expand upon our preliminary results and further investigate the novel role of mGluRs in preOL injury in developing cerebral white matter injury in vivo. Aim 3 will determine the molecular mechanisms of the interplay between iGluRs and mGluRs. We will examine whether mGluR modulation leads to changes in iGluR subunit expression, phosphorylation state, and internalization, and also investigate intracellular Ca2+ and oxidative stress, and the specific roles of signaling molecules such as Akt (protein kinase B), CaMKII (Ca2+/calmodulin kinase II), CaN (calcineurin), and PKC (protein kinase C) in the modulation of iGluR-mediated preOL injury by mGluRs. Completion of this project will help to elucidate novel mechanisms of hypoxic-ischemic preOL injury and to identify new targets for the development of therapeutic strategies to control preOL injury that underlies cerebral white matter disorders, such as PVL, for which no specific therapy currently exists. PUBLIC HEALTH RELEVANCE: Periventricular leukomalacia (PVL) is the predominant form of brain injury in the premature infant, and the most common cause of cerebral palsy. PVL affects up to 50% of the 56,000 premature infants born in the U. S. every year, yet currently no therapy exists for this serious human disorder. This project seeks to determine the mechanisms of the molecular interplay between ionotropic and metabotropic glutamate receptors in hypoxic- ischemic injury to the developing oligodendrocyte - the cellular substrate of PVL. The scientific knowledge to be acquired through this project is of likely benefit to the development of preventive strategies for PVL and the care of children with cerebral palsy.

描述（由申请人提供）：发育中的大脑缺氧缺血性损伤会导致毁灭性的神经系统后果。引人注目的是，缺氧缺血性脑损伤的模式高度依赖于年龄。在足月婴儿中，缺氧缺血主要影响大脑皮层，并伴有特征性神经元损失。然而，在早产儿中，缺氧缺血选择性地影响脑白质，对发育中的少突胶质细胞（OL）造成显着损伤，这种疾病称为脑室周围白质软化症（PVL）。发育中的 OL（髓鞘形成前 OL，称为“preOL”）非常容易受到缺氧缺血性损伤，并且是 PVL 的主要细胞基质。我们已经证明谷氨酸受体（GluR）的表达在体内和体外在OL上受到发育调节，离子型GluR（iGluR）介导前OL的缺氧缺血性损伤，但代谢型GluR（mGluR）可以调节这种损伤。然而，特异性 iGluR 和 mGluR 在缺氧缺血性 preOL 损伤中的作用及其信号传导机制仍然很大程度上未知。该提案的中心假设是 Ca2+ 渗透性 iGluR 介导缺氧缺血性 preOL 损伤，而第 1 组 mGluR 可以调节这种损伤，从而导致 iGluR 和 mGluR 之间的分子相互作用以及不同的受体后信号传导事件的整合。我们将重点关注确定 preOL 损伤中 iGluR 和 mGluR 之间串扰的机制。该项目的目标是为缺氧缺血性 preOL 损伤的年龄特异性机制提供新的见解，并确定治疗脑白质疾病基础上的 preOL 损伤的潜在年龄特异性治疗策略。该提案的目标 1 是确定 preOL 兴奋性毒性中 iGluR 功能和信号传导的改变序列，旨在确定特定的治疗可及靶点。目标 2 将扩展我们的初步结果，并进一步研究 mGluR 在 preOL 损伤中在体内发生脑白质损伤中的新作用。目标 3 将确定 iGluR 和 mGluR 之间相互作用的分子机制。我们将研究mGluR调节是否导致iGluR亚基表达、磷酸化状态和内化的变化，并研究细胞内Ca2+和氧化应激，以及信号分子如Akt（蛋白激酶B）、CaMKII（Ca2+/钙调蛋白）的具体作用激酶 II)、CaN（钙调神经磷酸酶）和 PKC（蛋白激酶 C）在 mGluR 调节 iGluR 介导的 preOL 损伤中的作用。该项目的完成将有助于阐明缺氧缺血性 preOL 损伤的新机制，并确定开发治疗策略的新目标，以控制脑白质疾病（例如 PVL）的 preOL 损伤，目前尚无具体治疗方法。 公共卫生相关性：脑室周围白质软化 (PVL) 是早产儿脑损伤的主要形式，也是脑瘫的最常见原因。美国每年出生的 56,000 名早产儿中，有 50% 受到 PVL 的影响，但目前尚无针对这种严重人类疾病的治疗方法。该项目旨在确定在发育中的少突胶质细胞（PVL 的细胞底物）缺氧缺血性损伤中离子型和代谢型谷氨酸受体之间分子相互作用的机制。通过该项目获得的科学知识可能有助于制定PVL预防策略和脑瘫儿童的护理。