COMPLEMENT AND THE BLOOD BRAIN BARRIER IN CEREBROVASCULAR DISEASE

脑血管疾病中的补体和血脑屏障

• 批准号: 6112465
• 负责人: WILLIAM HOLLANDER
• 金额: $ 20.46万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112465
• 关键词: Macaca fascicularis; SDS polyacrylamide gel electrophoresis; anaphylatoxins; atherosclerosis; autoradiography; blood brain barrier; cerebrovascular disorders; complement; dementia; dietary constituent; disease /disorder model; histopathology; hypercholesterolemia; hypertension; immunocytochemistry; immunoprecipitation; leukocyte activation /transformation; nutrition related tag; radioimmunoassay; western blottings

The overall aim of this proposal is to assess the participation of the complement system and other related plasma proteins in brain damage and vascular dementia caused by hypertension and/or cerebral vascular disease. The activation of the complement system results in the generation of biologically active peptides that are pro-inflammatory and cytotoxic and these include the anaphylatoxins, C3a, C4a and C5a; the opsonins C3b and C3bi and the membrane attack complex C5b-9. The specific aims of the proposal are: (1) to assess the integrity of the blood-brain barrier (BBB) in hypertensive, atherosclerotic and hypertension-atherosclerotic monkeys by Evan's blue leakage from the circulation and by immunochemical and immunocytochemical analyses of brain tissue for plasma proteins; (2) to determine whether complement proteins are extravasated with other plasma proteins into the brain tissue and undergo activation following the disruption of the BBB; (3) circulation and co-localize with complement in the brain tissue; (4) to identify the specific cell types and histological localization of these cell types that immunostain for complement or plasma proteins that might activate the complement system also leak from the circulation and co- localize with complement in the brain tissue; (4) to identify the specific cell types and histological localization of these cell types that immunostain for complement or plasma proteins in the brain tissue; (5) to correlate the disruption of the BBB and leakage of biologically active proteins with the histopathological changes in the brain. Four groups of mature male Cynomolgus monkeys will be studied consisting of a (1) normal control group, (2) hypertensive group, (3) atherosclerotic group and (4) hypertensive and atherosclerotic group. This experimental design will permit the study by (1) Evans blue leakage from the proteins and (3) immunochemical analyses of brain extracts for plasma proteins. Complement activation following the disruption of the BBB also will be assessed using specific antibodies to complement activation products. For immunocytochemistry, the Avidin-Biotin immunoperoxidase method will be used qualitatively and the immunostaining of plasma proteins and complement. The breakdown of the BBB and associated brain damage also will be correlated with the neuropathologic findings in the eyes and brain of the animals as well as the behavioral changes in the animals and other clinical findings. The proposed studies should enhance the understanding of the pathogenesis of brain damage and vascular dementia associated with hypertension and ischemic cerebral vascular disease.

这项建议的总体目标是评估 补体系统等相关血浆蛋白在脑损伤和脑损伤中的作用 高血压和/或脑血管疾病引起的血管性痴呆 疾病。补体系统的激活导致 产生具有促炎和抗炎作用的生物活性多肽 细胞毒性，包括过敏性毒素、C3a、C4a和C5a； 调理素C3b和C3bi以及膜攻击复合体C5b-9。这个 该提案的具体目标是：(1)评估 血脑屏障在高血压、动脉粥样硬化和高血压中的作用 高血压-动脉粥样硬化猴子的Evan‘s蓝渗漏 循环和通过免疫化学和免疫细胞化学分析 脑组织测定血浆蛋白；(2)测定补体 蛋白质与其他血浆蛋白质一起渗入大脑。 组织，并在血脑屏障被破坏后进行激活； 循环并与补体在脑组织中共定位；(4) 确定这些细胞的特定细胞类型和组织定位 补体或血浆蛋白免疫染色的细胞类型 激活补体系统也会从循环中渗漏出来 与补体在脑组织中定位；(4)识别 特定的细胞类型和这些细胞类型的组织定位 脑组织中补体或血浆蛋白的免疫染色； (5)血脑屏障破坏与生物渗漏的相关性 活性蛋白质与大脑中的组织病理学变化。四 将对成群的雄性食蟹猴进行研究，其中包括 A(1)正常对照组，(2)高血压组，(3)动脉粥样硬化 高血压合并动脉粥样硬化组。这项实验 设计将允许研究(1)埃文斯蓝从蛋白质中泄漏 (3)脑提取液中血浆蛋白的免疫化学分析。 血脑屏障中断后的补体激活也将 使用特定抗体来补充激活产物进行评估。 对于免疫细胞化学，亲和素-生物素免疫过氧化物酶方法将 可定性使用，血浆蛋白免疫染色和 互补性。血脑屏障的分解和相关的脑损伤也 会与眼部的神经病理结果相关联 动物的大脑以及动物和动物的行为变化 其他临床表现。建议的研究应可加强 对脑损伤和血管性痴呆发病机制的认识 与高血压和缺血性脑血管疾病有关。