Neuroglobin in Neuronal Hypoxi and Cerebral Ischemia

神经元缺氧和脑缺血中的神经球蛋白

• 批准号: 7589492
• 负责人: David Alan Greenberg
• 金额: $ 42.44万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589492
• 关键词: Affect; Binding; Blood; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain Ischemia; Cell Survival; Cerebral Infarction; Cerebral Ischemia; Cerebral Ischemia-Hypoxia; Cerebrum; Cobalt; DNA Damage; Deferoxamine; Disease; Dissociation; Globin; Goals; Hemoglobin; Hypoxia; In Vitro; Injury; Ischemic Brain Injury; Ischemic Neuronal Injury; Ischemic-Hypoxic Encephalopathy; Lead; Mediator of activation protein; Messenger RNA; Middle Cerebral Artery Occlusion; Molecular; Mus; Muscle; Myoglobin; Neuronal Hypoxia; Neuronal Injury; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitrogen; Nucleotides; Oxygen; Peroxonitrite; Proteins; Research; Resistance; Response Elements; Role; Severities; Stroke; Testing; Transgenic Mice; Tyrosine; Work; base; cytotoxic; hypoxia inducible factor 1; in vivo; knock-down; nervous system disorder; neuroglobin; neuroprotection; nitration; novel therapeutics; overexpression; prevent; protective effect; protein expression; public health relevance; research study; transcription factor

DESCRIPTION (provided by applicant): Cerebral hypoxia and ischemia trigger endogenous protective mechanisms that can prevent or limit brain damage. Understanding these mechanisms may lead to new therapeutic strategies for stroke and related disorders. Neuroglobin (Ngb), a recently discovered monomeric globin that is distantly related to hemoglobin and myoglobin, is expressed predominantly in brain neurons, and appears to modulate hypoxic-ischemic brain injury. We have found that neuronal hypoxia and cerebral ischemia induce Ngb expression, that enhancing Ngb expression reduces and knocking down Ngb expression increases hypoxic neuronal injury in vitro and ischemic cerebral injury in vivo, and that Ngb-overexpressing transgenic mice are resistant to cerebral infarction from occlusion of the middle cerebral artery. However, the mechanisms that underlie hypoxic induction of neuroprotection by Ngb are unknown. This application is based on the hypothesis that Ngb is a key mediator of endogenous neuroprotection from hypoxic-ischemic injury, and has the long-term goal of identifying new treatments for stroke. The specific aims of the proposed project are to: (1) Determine the role of hypoxia-inducible factor-1 (HIF-1) in hypoxic induction of Ngb expression in vitro; (2) Determine how Ngb protects neurons against hypoxia in vitro; and (3) Evaluate the extent to which mechanisms for hypoxic induction of Ngb and protection from hypoxia by Ngb in vitro are recapitulated during focal cerebral ischemia in vivo. PUBLIC HEALTH RELEVANCE: Neuronal hypoxia and brain ischemia activate protective mechanisms, and understanding these mechanisms may lead to new treatments for stroke. Neuroglobin (Ngb), a recently discovered protein related to blood hemoglobin and muscle myoglobin, is found primarily in the brain. In previous work, we found that hypoxia and ischemia increase Ngb expression, that this reduces hypoxic and ischemic neuronal injury, and that mice overexpressing Ngb are resistant to experimental stroke. In this application, we propose to investigate the mechanisms involved in the induction of Ngb expression and in Ngb's protective effects, concentrating on the roles of hypoxia-inducible factor-1 and nitric oxide synthases. The goal of this research is to find new ways to treat stroke and related neurological disorders.

描述（由申请人提供）：脑缺氧和缺血触发内源性保护机制，可以预防或限制脑损伤。了解这些机制可能会导致中风和相关疾病的新治疗策略。神经球蛋白（Ngb）是最近发现的一种单体球蛋白，与血红蛋白和肌红蛋白关系较远，主要在脑神经元中表达，似乎可以调节缺氧缺血性脑损伤。我们发现神经元缺氧和脑缺血会诱导Ngb表达，增强Ngb表达会减少和敲除Ngb表达会增加体外缺氧神经元损伤和体内缺血性脑损伤，并且Ngb过表达的转基因小鼠对大脑中动脉闭塞引起的脑梗塞具有抵抗力。然而，Ngb 缺氧诱导神经保护的机制尚不清楚。该申请基于这样的假设：Ngb 是内源性神经保护免受缺氧缺血性损伤的关键介质，其长期目标是确定中风的新疗法。该项目的具体目标是：（1）确定缺氧诱导因子1（HIF-1）在体外缺氧诱导Ngb表达中的作用； （2）确定Ngb如何在体外保护神经元免受缺氧影响； (3)评估体外局灶性脑缺血期间Ngb缺氧诱导和Ngb防止缺氧的机制在多大程度上重现。公共卫生相关性：神经元缺氧和脑缺血会激活保护机制，了解这些机制可能会带来中风的新治疗方法。神经红蛋白（Ngb）是最近发现的一种与血液血红蛋白和肌肉肌红蛋白相关的蛋白质，主要存在于大脑中。在之前的工作中，我们发现缺氧和缺血会增加Ngb的表达，这会减少缺氧和缺血性神经元损伤，并且过度表达Ngb的小鼠对实验性中风具有抵抗力。在本申请中，我们打算研究 Ngb 表达诱导和 Ngb 保护作用的机制，重点研究缺氧诱导因子 1 和一氧化氮合酶的作用。这项研究的目标是寻找治疗中风和相关神经系统疾病的新方法。