Homocysteine-mediated Cerebral Microvascular Damage

同型半胱氨酸介导的脑微血管损伤

• 批准号: 7105435
• 负责人: JUSTIN L MASSENGALE
• 金额: $ 5.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-14 至 2007-07-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105435
• 关键词: apoptosis; biological signal transduction; capillary; cerebral ischemia /hypoxia; enzyme activity; free radical oxygen; free radical scavengers; homocysteine; laboratory mouse; lactate dehydrogenases; metalloendopeptidases; microcirculation; pathologic process; postdoctoral investigator; protein quantitation /detection; stroke; superoxide dismutase; tissue /cell culture; vascular endothelium; western blottings

DESCRIPTION (provided by applicant): This study investigates relationships between apoptotic cell death pathways, reactive oxygen species, and matrix metalloproteases in the mechanism of cerebral endothelial cell injury that results from exposure to elevated levels of homocysteine, a known risk factor for stroke. Homocysteine-induced injury in cultured mouse cerebral microvascular endothelial cells will be determined using cell death assays including lactate dehydrogenase release, and changes in expression of specific proteins of the apoptosis and cell-survival pathways will be measured using Western immunoblotting. Matrix metalloproteinase secretion will be additionally determined using gelatin zymography. Results will be compared between wild-type cells and those overexpressing superoxide dismutase-1, to study the involvement of oxygen radical scavenging in homocysteine-induced injury, as has been confirmed in the pathogenesis of cerebral ischemic damage. Such understanding can help elucidate mechanisms shared between ischemic and homocysteine-related injury, and might ultimately lead to novel strategies for stroke prevention and treatment through therapies targeted at points in the homocysteine injury pathway.

描述（由申请人提供）：本研究调查了由于暴露于高水平的同型半胱氨酸（已知的中风危险因素）导致的脑内皮细胞损伤机制中凋亡细胞死亡途径、活性氧和基质金属蛋白酶之间的关系。使用包括乳酸脱氢酶释放在内的细胞死亡测定来确定培养的小鼠脑微血管内皮细胞中同型半胱氨酸诱导的损伤，并使用蛋白质免疫印迹来测量细胞凋亡和细胞存活途径的特定蛋白表达的变化。基质金属蛋白酶的分泌将另外使用明胶酶谱法测定。将比较野生型细胞和超氧化物歧化酶-1过表达细胞的结果，以研究氧自由基清除在同型半胱氨酸诱导的损伤中的作用，这在脑缺血损伤的发病机制中已得到证实。这种理解可以帮助阐明缺血性损伤和同型半胱氨酸相关损伤之间共有的机制，并可能最终通过针对同型半胱氨酸损伤途径中的点的治疗产生预防和治疗中风的新策略。