Neuroglobin in Neuronal Hypoxi and Cerebral Ischemia

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（Neuroglobin, Ngb）是最近发现的一种单体球蛋白，与血红蛋白和肌红蛋白有较远的亲缘关系，主要在脑神经元中表达，并似乎调节缺氧缺血性脑损伤。我们发现神经元缺氧和脑缺血诱导Ngb表达，Ngb表达增强可减少Ngb表达，抑制Ngb表达可增加体外缺氧神经元损伤和体内缺血性脑损伤，过表达Ngb的转基因小鼠对大脑中动脉闭塞性脑梗死具有抵抗性。然而，Ngb在缺氧诱导下的神经保护机制尚不清楚。这项应用是基于Ngb是缺氧缺血性损伤内源性神经保护的关键介质的假设，并具有确定中风新治疗方法的长期目标。拟建项目的具体目的是：(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在体外对神经元缺氧的保护作用；(3)评估在体内局灶性脑缺血时，Ngb在体外诱导缺氧的机制和Ngb对缺氧的保护作用在多大程度上得到概括。公共卫生相关性：神经元缺氧和脑缺血激活保护机制，了解这些机制可能导致中风的新治疗方法。神经红蛋白（Ngb）是最近发现的一种与血红蛋白和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，从而减少缺氧和缺血性神经元损伤，并且过表达Ngb的小鼠对实验性脑卒中具有抵抗性。在这项应用中，我们拟研究Ngb诱导表达的机制和Ngb的保护作用，重点研究缺氧诱导因子-1和一氧化氮合酶的作用。这项研究的目的是寻找治疗中风和相关神经系统疾病的新方法。

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.