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: 7795706
• 负责人: Wenbin Deng
• 金额: $ 27.29万
• 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/7795706
• 关键词: Acids; Address; Adverse effects; Affect; Age; Agonist; Animal Model; Antibodies; Attenuated; Awareness; Behavioral; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Budgets; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcineurin; Cell Death; Cells; Cerebral Palsy; Cerebral cortex; Cerebrum; Characteristics; Child Care; Critiques; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Equilibrium; Event; Figs - dietary; Gene Mutation; Gene Transfer; Glutamate Receptor; Goals; Hand; Human; Hypoxia; In Situ; In Vitro; Infant hypoxia; Injury; Intervention; Investigation; Ischemic-Hypoxic Encephalopathy; Knowledge; Laboratories; Maps; Mediating; Metabotropic Glutamate Receptors; Modeling; Molecular; Molecular Target; Monitor; N-Methylaspartate; Names; Neurologic; Oligodendroglia; Outcome; Oxidative Stress; Pattern; Periventricular Leukomalacia; Permeability; Pharmacodynamics; Phosphorylation; Play; Postdoctoral Fellow; Predisposition; Premature Infant; Preparation; Prevention strategy; Principal Investigator; Property; Protein Kinase C; Proto-Oncogene Proteins c-akt; Publications; Published Comment; Rattus; Receptor Signaling; Recruitment Activity; Regulation; Research Personnel; Role; Signal Transduction; Signaling Molecule; System; Therapeutic; Time; Toxic effect; Translations; Virus; Western Blotting; age related; base; excitotoxicity; experience; in vivo; innovation; insight; kainate; neuron loss; neuroprotection; neurotransmission; novel; novel therapeutics; pre-clinical; prevent; programs; public health relevance; receptor; receptor expression; research study; response; success; therapeutic development; 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。令人惊讶的是，缺氧 - 缺血性脑损伤的模式高度依赖于年龄。在期限婴儿中，低氧 - 缺血性主要影响具有特征性神经元丧失的脑皮质。然而，在早产儿中，缺氧 - 缺血选择性影响脑白质，并因发育中的少突胶质细胞（OL）显着损伤，这是一种称为脑室周围白细胞室（PVL）的疾病。发育中的OL（称为“ preol”）的OL高度容易受到低氧 - 缺血性损伤的影响，并且是PVL的主要细胞底物。我们已经表明，谷氨酸受体（GLUR）表达在体内和体外对OLS的发育调节，并且离子胶质（iGlurs）介导了preols的缺氧 - 异化性损伤，但代替型粘着（MGLURS）可以调节这种损伤。然而，特定的iGlurs和mglurs在低氧 - 缺血性preol损伤中的作用以及信号传导机制在很大程度上尚不清楚。该提案的中心假设是Ca2+可渗透的iGlurs介导缺氧 - 缺血性preol损伤，而第1组MGLUR可以调节这种损伤，需要iGlurs和mglurs之间的分子相互作用，并在不同的后后受体信号传导事件的整合。我们将重点介绍在Preol损伤中iGlurs和mglurs之间的串扰机理。该项目的目的是提供有关低氧 - 缺血性preol损伤的特定年龄特异性机制的新见解，并确定治疗脑白质疾病构成的PEROL损伤的潜在特定年龄特异性治疗策略。该提案的目的1是确定iGlur功能和信号转导的序列，旨在确定特定的特定治疗范围可访问的靶标。 AIM 2将扩大我们的初步结果，并进一步研究mglurs在Preol损伤中的新作用在体内发展脑白质损伤中。 AIM 3将确定iGlurs和mglurs之间相互作用的分子机制。 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 MGLURS对Iglur介导的PEROL损伤的调节。该项目的完成将有助于阐明缺氧性缺血性preol损伤的新机制，并确定新的靶标，以开发治疗策略，以控制PEROL损伤，这些策略是脑白质疾病构成的PREOL损伤，例如PVL，目前尚无特定的治疗。 公共卫生相关性：周围白细胞藻（PVL）是早产婴儿的主要脑损伤形式，也是脑瘫的最常见原因。 PVL每年在美国出生的56,000名早产婴儿中，多达50％，但目前尚无治疗这种严重的人类疾病。该项目旨在确定缺氧 - 缺血性缺血性损伤对发育中的少突胶质细胞 - PVL的细胞底物中的离子型和代谢性谷氨酸受体之间的分子相互作用的机制。通过该项目获得的科学知识可能对PVL预防策略的制定和脑瘫儿童的护理有益。