MECHANISMS OF COMPLEMENT INDUCED ENDOTHELIAL DYSFUNCTION

描述：（改编自申请人摘要） 最近对补体蛋白的激活产生了相当大的兴趣 在心肌缺血和再灌注的早期阶段。 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。 他们提供了很好的证据，证明缺氧本身并不能激活 相反，再灌注和氧自由基产生C5 b， C5 b-9膜攻击复合物顺序组装的关键。 这种跨膜孔复合物可直接损伤血管 内皮细胞通过多种机制，包括产生氧气 代谢物。 C5 a片段的作用预计涉及 中性粒细胞的协同活化复合血管损伤。 的 五年计划包括实验研究补充 孤立血管中的机制（包括大血管和微血管，1年 缺氧-复氧后补体沉积的验证 对小和大冠状动脉血管和内皮细胞的影响（年 3），最后描绘了替代补体途径， 猪心肌缺血再灌注模型，特别强调 对C5 b-9介导的体内损伤的治疗性衰减的影响。

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.