Neuroglobin in Neuronal Hypoxi and Cerebral Ischemia

神经元缺氧和脑缺血中的神经球蛋白

基本信息

批准号：
8399022
负责人：
David Alan Greenberg
金额：
$ 40.13万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8399022
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 Hypoxis In Vitro Injury Ischemic Brain Injury Ischemic Neuronal Injury Ischemic-Hypoxic Encephalopathy Lead Mediator of activation protein 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 mRNA Expression nervous system disorder neuroglobin neuroprotection nitration novel therapeutics overexpression prevent protective effect protein expression research study transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT 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 an 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.

项目摘要/摘要脑缺氧和缺血触发内源性保护机制，可以预防或限制大脑损害。了解这些机制可能会导致中风和相关的新治疗策略疾病。 Neuroglobin（NGB），最近发现的单体球蛋白，与血红蛋白息息相关肌红蛋白主要在脑神经元中表达，并且似乎调节缺氧性缺血性脑损伤。我们发现神经元缺氧和脑缺血诱导NGB表达，即增强NGB表达会减少和敲低NGB表达，从而增加了缺氧神经元损伤体内体外和缺血性脑损伤，而过表达NGB的转基因小鼠对大脑中动脉阻塞的脑梗塞。但是，基于的机制 NGB对神经保护的低氧诱导尚不清楚。该应用程序基于以下假设 NGB是缺氧性损伤因内源性神经保护的关键介体，并且长期具有确定中风的新疗法的目标。拟议项目的具体目的是：（1）确定缺氧诱导因子-1（HIF-1）在体外NGB表达的缺氧诱导中的作用；（2）确定 NGB如何在体外保护神经元免受缺氧的侵害；（3）评估对哪种机制的程度在局灶性大脑期间概括了NGB对NGB的缺氧诱导和防止缺氧的保护体内缺血。