Endothelial vascular injury

内皮血管损伤

• 批准号: 6809066
• 负责人: PAK H CHAN
• 金额: $ 21.01万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6809066
• 关键词: antioxidants; biological signal transduction; blood brain barrier; cell death; cellular pathology; cerebral ischemia /hypoxia; disease /disorder model; enzyme activity; free radical oxygen; genetically modified animals; inflammation; laboratory mouse; membrane permeability; mitochondria; neuropathology; oxidative stress; reperfusion; stroke; superoxide dismutase; tissue /cell culture; vascular endothelium

The blood-brain (BBB), whose hallmark is its impermeability, is formed by the brain microvascular endothelium. With the occurrence of a noxious stimulus, activated endothelial cells produce reactive oxygen species (ROS) and release inflammatory mediators. Accumulating evidence suggests that ROS can alter BB permeability and induce cerebral edema and tissue damage, and that the cerebral microvasculature and inflammatory cells are critically involved in this oxidative stress-mediated process. ROS such as superoxide anion are involved in the initiation of immediate cell damage during brain ischemia and injury, as well as in the modulation of cellular signaling and control of gene expression. Thus, antioxidant enzymes that control ROS production possess the ability to effectively modulate the development of brain damage after an insult. The successful development of genetically manipulated mice deficient in or over-expressing the constitutively expressed cytosolic antioxidant, copper/zinc-superoxide dismutase (SOD1), or the inducible mitochondrial antioxidant, manganese-SOD (SOD2), offers a unique opportunity to elucidate, in a molecular fashion, the oxidative mechanisms in brain injury following stroke and mitochondria-related BB dysfunction. Using SOD1- and SOD2-knock-out mutant mice, in addition to SOD1-over-expressors (transgenic[Tg]) and the recently developed SOD2 Tg mice, we will explore the molecular basis of endothelial cell function and injury in the central nervous system. Additionally, we will examine the relationship between mitochondrial dysfunction and microvascular permeability, and the contribution of ROS-induced BBB damage by inflammatory cells. To that end, we will use both in vivo models (transient focal cerebral ischemia and 3-nitroproprionic acid [3-NP-]-induced mitochondrial excitotoxicity) and in vitro (cell culture and microvessel isolation) systems. We believe these are unique and fresh approaches that will provide insights into the oxidative mechanisms of mitochondrial dysfunction that underlies cerebrovascular endothelial cell death/survival in transient focal cerebral ischemia and in 3-NP-induced striatal injury.

血脑（BBB）的标志是其不渗透性，由脑微血管内皮形成。随着有害刺激的发生，活化的内皮细胞会产生活性氧（ROS）和释放炎症介质。积累的证据表明，ROS可以改变BB的渗透性并诱导脑水肿和组织损伤，并且脑微血管和炎性细胞与这种氧化应激介导的过程非常重要。 ROS（例如超氧化物阴离子）参与脑缺血和损伤期间的直接细胞损伤以及基因表达的细胞信号传导和控制的调节。因此，控制ROS产生的抗氧化剂具有有效调节侮辱后脑损伤发展的能力。在组成型表达或过度表达的遗传操纵小鼠的成功发展中，氧化剂，铜/锌 - 氧化剂歧化酶（SOD1）或可诱导的线粒体抗氧化剂抗氧化剂（SOD2）提供了一种独特的机制，以实现脑部的机制，以介导的型机制，以诱导的方式进行介绍，并提供型独特的时尚，从线粒体相关的BB功能障碍。除了SOD1-和SOD2敲除突变小鼠外，除了SOD1超过表达器（转基因[TG]）和最近开发的SOD2 TG小鼠外，我们还将探索中枢神经系统内皮细胞功能和损伤的分子基础。此外，我们将研究线粒体功能障碍与微血管通透性之间的关系，以及炎症细胞对ROS诱导的BBB损伤的贡献。为此，我们将使用体内模型（瞬时局灶性脑缺血和3硝基抗蛋白酸[3-NP-] - 诱导的线粒体兴奋性毒性）和体外（细胞培养和微型分离）系统。我们认为，这些是独特而新鲜的方法，可以为线粒体功能障碍的氧化机制提供见解，这些功能障碍是脑血管内皮细胞死亡/瞬时局灶性脑脑部缺血和3-NP诱导的术语损伤的基础。