Neuroglobin in Neuronal Hypoxi and Cerebral Ischemia

项目总结/摘要 脑缺氧和缺血触发内源性保护机制，可以防止或限制脑缺血 损害了解这些机制可能会导致中风和相关疾病的新治疗策略 紊乱脑红蛋白（Ngb）是最近发现的一种单体球蛋白，与血红蛋白有远亲关系 和肌红蛋白，主要在脑神经元中表达，并且似乎调节缺氧缺血性 脑损伤我们已经发现神经元缺氧和脑缺血诱导Ngb表达， 增强Ngb表达减少和敲低Ngb表达增加缺氧性神经元损伤， 体外和体内缺血性脑损伤，且Ngb过表达转基因小鼠对 大脑中动脉闭塞引起的脑梗死。然而， Ngb对神经保护缺氧诱导作用是未知的。本申请基于以下假设： Ngb是缺氧缺血性损伤内源性神经保护的关键介质， 目的是找到治疗中风的新方法。建议项目的具体目标是：（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;以及（3）评估Ngb的机制在多大程度上 脑缺血缺氧诱导Ngb和Ngb对缺氧的保护作用 体内缺血。

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.