MECHANISMS OF COMPLEMENT INDUCED ENDOTHELIAL DYSFUNCTION

描述：(改编自申请人的摘要)有 近来人们对补体蛋白的激活很感兴趣 在心肌缺血再灌流的早期阶段。在 目前，该研究小组继续专注于内皮细胞 损伤，特别强调替代补体途径。 它们提供了很好的证据，证明仅靠缺氧并不能激活 相反，再灌流和氧自由基产生C5b， C5b-9膜攻击复合体顺序组装的关键。 这种跨膜孔复合体可以直接损伤血管 内皮通过多种机制，包括氧气的产生 代谢物。C5a片段的作用预计涉及 中性粒细胞协同激活复合血管损伤。这个 五年计划包括实验研究补充性 孤立血管的机制(包括大血管和微血管，第1年 2)低氧-复氧后补体沉积的验证 关于冠状动脉大小血管和内皮细胞(年 3)，最后描述了可供选择的补体途径 猪心肌缺血再灌流模型的研究 C5b-9介导的体内损伤的治疗减毒作用

DESCRIPTION: (Adapted from the applicant's abstract) There is considerable recent interest in the activation of complement proteins during the early stages of myocardial ischemia and reperfusion. In the present proposal this research team continue their focus on endothelial injury, with particular emphasis on the alternative complement pathway. They provide excellent evidence that hypoxia alone does not activate this cascade; rather, reperfusion and oxygen radicals produce C5b, the linchpin for sequential assembly of the C5b-9 membrane attack complex. This transmembrane pore complex could directly injure vascular endothelium by a number of mechanisms, including production of oxygen metabolites. The role of the C5a fragments is projected to involve synergistic activation of neutrophils compounding vascular injury. The five year proposal consists of experiments investigating complement mechanisms in isolated vessels (both large and micro-vessels, years 1 and 2), verification of complement deposition after hypoxia-reoxygenation on small and large coronary artery vessels and endothelial cells (year 3), and lastly delineation of the alternative complement pathways during myocardial ischemia-reperfusion in a pig model, with special emphasis on therapeutic attenuation of C5b-9 mediated injury in vivo.