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）是由脑微血管内皮细胞形成的，其特点是具有不可渗透性。随着有害刺激的发生，活化的内皮细胞产生活性氧（ROS）并释放炎症介质。越来越多的证据表明，ROS可以改变BB的渗透性，并诱导脑水肿和组织损伤，脑微血管和炎症细胞在这个氧化应激介导的过程中是至关重要的。ROS如超氧阴离子参与脑缺血和损伤期间立即细胞损伤的起始，以及参与细胞信号传导的调节和基因表达的控制。因此，控制ROS产生的抗氧化酶具有在损伤后有效调节脑损伤发展的能力。基因操作的小鼠缺乏或过度表达的组成性表达的胞质抗氧化剂，铜/锌-超氧化物歧化酶（SOD 1），或诱导型线粒体抗氧化剂，锰-SOD（SOD 2）的成功开发，提供了一个独特的机会，阐明，在分子方式，脑损伤后中风和脑卒中相关的BB功能障碍的氧化机制。使用SOD 1和SOD 2敲除突变小鼠，以及SOD 1过表达小鼠（转基因[Tg]）和最近开发的SOD 2 Tg小鼠，我们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和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（短暂局灶性脑缺血和3-硝基丙酸[3-NP-]诱导的线粒体兴奋性毒性）和体外（细胞培养和微血管分离）系统。我们相信，这些是独特的和新鲜的方法，将提供深入了解线粒体功能障碍的氧化机制，脑血管内皮细胞死亡/生存短暂局灶性脑缺血和3-NP诱导的纹状体损伤的基础。