Role of Complement CRP complexes in Inflammation and Organ Dysfunction

补体 CRP 复合物在炎症和器官功能障碍中的作用

• 批准号: 68339076
• 负责人: Professor Dr. Peter F. Zipfel
• 金额: --
• 依托单位: Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. Hans-Knöll-Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/68339076?language=en
• 关键词: Role; Complement; CRP; complexes; Inflammation

Trauma induces inflammation and tissue- as well as cell damage. The initial insult causes activation of the complement cascade which orchestrates inflammation and tissue destruction. Complement plays an important role in the clearance of trauma induced damaged cells and of apoptotic and necrotic particles. This elimination is enhanced by the soluble acute phase protein C-reactive protein (CRP). In this project we plan to study the interaction of the soluble complement inhibitor Factor H with CRP and the function of the Factor H:CRP complex during trauma and inflammation. We propose a role of this complex in the clearance of damaged particles. Apparently at the surface of damaged particles complement activation proceeds to C3 deposition, but further progression of the is inhibited. The later step is blocked by binding of the soluble complement inhibitors Factor H and C4BP, which attach to the surface of damaged cells in combination with CRP. In addition the role of two novel CRP ligands, the Factor H related proteins FHR-4A and FHR-4B will be studied. Most likely by complexing CRP all three complement regulators (Factor H, FHR-4A and FHR-4B) block amplification of the complement cascade on the surface of damaged cells, inhibit inflammation and allow removal by phagocytes. The understanding of these mechanisms will help to define appropriate complement inhibitors in order to modulate these reactions.

创伤引起炎症和组织-以及细胞损伤。最初的损伤引起补体级联的激活，其协调炎症和组织破坏。补体在清除创伤诱导的受损细胞以及凋亡和坏死颗粒中起重要作用。可溶性急性时相蛋白C反应蛋白（CRP）可增强这种消除。在这个项目中，我们计划研究可溶性补体抑制剂H因子与CRP的相互作用以及H因子：CRP复合物在创伤和炎症中的功能。我们提出了这个复杂的清除受损颗粒的作用。显然，在受损颗粒的表面，补体激活进行到C3沉积，但进一步的进展受到抑制。后一步骤被可溶性补体抑制剂H因子和C4 BP的结合所阻断，所述补体抑制剂与CRP结合附着于受损细胞的表面。此外，还将研究两种新的CRP配体，即因子H相关蛋白FHR-4A和FHR-4 B的作用。最有可能的是，通过复合CRP，所有三种补体调节剂（因子H、FHR-4A和FHR-4 B）阻断受损细胞表面上补体级联的扩增，抑制炎症并允许被吞噬细胞清除。了解这些机制将有助于确定适当的补体抑制剂，以调节这些反应。