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）是由脑微血管内皮形成的，其特点是其不渗透性。当有害刺激发生时，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，活性氧可以改变脑屏障的通透性，诱导脑水肿和组织损伤，并且脑微血管和炎症细胞在这一氧化应激介导的过程中起关键作用。超氧阴离子等活性氧参与脑缺血损伤时细胞立即损伤的启动，并参与细胞信号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有效调节损伤后脑损伤发展的能力。成功培养了缺乏或过度表达组成表达的细胞质抗氧化剂铜/锌超氧化物歧化酶（SOD1）或诱导线粒体抗氧化剂锰超氧化物歧化酶（SOD2）的基因操纵小鼠，为从分子角度阐明脑卒中后脑损伤和线粒体相关BB功能障碍的氧化机制提供了独特的机会。利用SOD1-和SOD2敲除突变小鼠，以及SOD1过表达者（转基因[Tg]）和最近开发的SOD2 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与微血管通透性之间的关系，以及炎症细胞在ros诱导的血脑屏障损伤中的作用。为此，我们将使用体内模型（短暂局灶性脑缺血和3-硝基本体酸[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。我们相信这些独特而新颖的方法将为线粒体功能障碍的氧化机制提供见解，线粒体功能障碍是短暂局灶性脑缺血和3- np诱导纹状体损伤中脑血管内皮细胞死亡/存活的基础。