COMPLEMENT AND THE BLOOD BRAIN BARRIER IN CEREBROVASCULAR DISEASE

本提案的总体目标是评估 补体系统和其他相关血浆蛋白在脑损伤中的作用， 由高血压和/或脑血管性疾病引起的血管性痴呆 疾病 补体系统的激活导致 产生促炎的生物活性肽， 细胞毒性，这些包括过敏毒素，C3 a，C4 a和C5 a; 调理素C3 b和C3 bi以及膜攻击复合物C5 b-9。 的 建议的具体目标是：（1）评估 血脑屏障（BBB）在高血压、动脉粥样硬化和 高血压-动脉粥样硬化的猴子通过埃文的蓝色泄漏从 免疫化学和免疫细胞化学分析， 脑组织血浆蛋白;（2）确定是否补体 蛋白质与其他血浆蛋白质一起外渗到大脑中 组织并在破坏BBB后经历活化;（3） 循环并与脑组织中的补体共定位;（4） 确定这些细胞的特定细胞类型和组织学定位， 免疫染色补体或血浆蛋白的细胞类型， 激活补体系统也从循环和共同泄漏， 在脑组织中定位补体;（4）识别 特定的细胞类型和这些细胞类型的组织学定位 对脑组织中的补体或血浆蛋白进行免疫染色; (5)为了将血脑屏障的破坏和生物学上的渗漏联系起来， 活性蛋白与脑组织病理学改变的关系。 四 将研究成年雄性食蟹猴组，包括 a（1）正常对照组，（2）高血压组，（3）动脉粥样硬化组 （4）高血压合并动脉粥样硬化组。 该实验 设计将允许通过以下方式进行研究：（1）蛋白质的伊文思蓝渗漏 （3）脑提取物的血浆蛋白免疫化学分析。 BBB破坏后的补体激活也将被抑制。 使用补体激活产物的特异性抗体进行评估。 对于免疫细胞化学，亲和素-生物素免疫过氧化物酶法将 用于定性和血浆蛋白的免疫染色， 补体 血脑屏障的破坏和相关的脑损伤也 将与眼睛中的神经病理学发现相关， 动物的大脑以及动物的行为变化， 其他临床发现。 拟议的研究应加强 了解脑损伤和血管性痴呆的发病机制 与高血压和缺血性脑血管病有关。

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.