Characterisation of antioxidant pathways involving Gpx-1: Implications for neural ischemic reperfusion injury.

涉及 Gpx-1 的抗氧化途径的表征：对神经缺血再灌注损伤的影响。

• 批准号: nhmrc : 236866
• 负责人: A/Pr Peter Crack
• 金额: $ 30.56万
• 依托单位: Monash University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/characterisation-antioxidant-pathways-reperfusion-injury/95967
• 关键词: Characterisation; antioxidant; pathways; involving; Gpx

Neural damage following stroke can be grouped into two stages. The first occurs immediately following the ischemic insult and results in the rapid loss of neural cell viability; the second stage (which usually results in severe neural dysfunction) occurs over many hours following reperfusion. There is however, a window of opportunity shortly following the ischemia-reperfusion where damage to the brain can be minimized if appropriate therapeutic intervention was available. However, our ability to identify novel targets and devise strategies for the treatment of stroke relies on our understanding of (a) the molecular processes that are initiated following brain ischemia and (b) the delayed molecular events that follow reperfusion and hypoperfusion and result in extensive neuronal loss. A major component that accompanies stroke is the generation of oxidative stress. Reactive oxygen species (ROS) are thought to make a significant contribution to neuronal cell injury and death during both the early and late stages following ischemia. Therefore the molecular pathways that are involved in ROS generation are prime targets for the development of improved therapies. It has already been established by us that the antioxidant enzyme, glutathione peroxidase-1 (Gpx-1) is essential in protecting neurons from ischemic injury-death. A clearer understanding of how Gpx-1 confers this protection in vivo would make an important contribution towards the design of improved treatments. In this proposal, we plan to determine the role of Gpx-1 in an in vivo model of stroke to: (1) demonstrate in a broader sense the functional importance of this antioxidant enzyme in neuronal survival and (2) to demonstrate in a more specific manner, the impact of this enzyme on two signaling molecules, PI3kinase (PI3K) and NFkB (both of which are redox sensitive and play important roles in neuronal cell viability) and their relevance to ischemic cell injury and death.

中风后的神经损伤可以分为两个阶段。第一阶段在缺血损伤后立即发生，导致神经细胞活力迅速丧失；第二阶段(通常导致严重的神经功能障碍)发生在再灌注后数小时以上。然而，如果有适当的治疗干预措施，在缺血再灌注后不久就有机会将对大脑的损害降至最低。然而，我们识别新靶点和设计中风治疗策略的能力依赖于我们对以下方面的理解：(A)脑缺血后启动的分子过程；(B)再灌流和低灌流后导致广泛神经元丢失的延迟分子事件。伴随中风的一个主要组成部分是氧化应激的产生。在缺血的早期和晚期，活性氧物种(ROS)被认为对神经细胞的损伤和死亡起着重要作用。因此，参与ROS产生的分子途径是改进疗法发展的主要靶点。我们已经证实，抗氧化酶谷胱甘肽过氧化物酶-1(GPX-1)在保护神经元免受缺血损伤-死亡中是必不可少的。更清楚地了解GPX-1是如何在体内提供这种保护的，将对改进治疗的设计做出重要贡献。在这项建议中，我们计划确定GPX-1在中风体内模型中的作用，以：(1)在更广泛的意义上证明这种抗氧化酶在神经元存活中的功能重要性；(2)以更具体的方式证明该酶对两种信号分子PI3K(PI3K)和NFkB(这两种信号分子都是氧化还原敏感的，在神经细胞活性中发挥重要作用)的影响及其与缺血细胞损伤和死亡的相关性。