Role of complement regulator properdin in the interaction between platelets and l

补体调节剂备解素在血小板和 l 相互作用中的作用

• 批准号: 8860236
• 负责人: Viviana P Ferreira
• 金额: $ 37.31万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-04 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860236
• 关键词: Address; Alternative Complement Pathway; Binding; Biological Assay; Blood; Blood Cells; Blood Platelets; Blood Vessels; Blood flow; C3bi; Cardiovascular Diseases; Cell Aggregation; Cells; Chronic; Collagen; Complement; Complement 3 Convertase; Complement 3a; Complement 3b; Complement 5a; Complement Activation; Complement Factor H; Complement Inactivators; Country; Data; Deposition; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Generations; Health; Hemostatic function; Human; In Situ; Inflammatory; Injury; Knockout Mice; Lead; Length; Leukocytes; Ligands; Liquid substance; Mediating; Molecular; Molecular Biology Techniques; Monoclonal Antibodies; Mus; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Phase; Physiological; Play; Properdin; Recombinants; Regulation; Reporting; Rest; Role; Site; Surface; Surface Plasmon Resonance; System; Therapeutic; Thrombosis; Thrombus; Tissues; Vascular Diseases; Whole Blood; Woman; Work; base; complement system; design; in vivo; inhibitor/antagonist; intravital microscopy; men; mortality; mutant; neutrophil; novel; prevent; response; shear stress; vascular inflammation; venule

DESCRIPTION (provided by applicant): In the U.S., cardiovascular disease is the leading cause of mortality in men and women. Patients with inflammatory cardiovascular disease have an increased number of circulating activated platelets and platelet/leukocyte aggregates, both of which play a central role in the initiation and progression of disease. Activated platelets promote the initiation and propagation of the complement system on their surface, leading to vascular inflammation and thrombosis. We have recently reported a molecular mechanism by which properdin, a positive regulator of the alternative pathway of complement, binds directly to activated, but not to resting platelets, independently from C3b, and initiates complement activation. Our novel preliminary data demonstrate ex-vivo that human properdin increases platelet/leukocyte aggregate formation and the development of collagen-induced thrombi in whole blood subjected to shear stress. Inhibition of properdin binding to C3b and to cells significantly reduces both outcomes. The mechanisms underlying how properdin stimulates the interaction between platelets and leukocytes are unknown and the objective of this proposal is to define these mechanisms. Properdin is produced mainly by activated leukocytes. In inflammatory microenvironments, activated leukocytes and platelets directly interact with one another, and the leukocyte- derived properdin would be available to platelets at high concentrations. We hypothesize that properdin enhances the interaction between platelets and leukocytes via complement alternative pathway-dependent mechanisms including, at least in part, properdin-initiated complement activation, as well as via mechanisms that do not depend on complement activation (i.e. serving as a bridge between cells). To address this hypothesis we propose the following aims: (1) To determine how the interaction of properdin with C3b as well as with platelets and leukocytes can be inhibited in order to prevent, on these cells, properdin-mediated stabilization of convertases or properdin-initiated complement activation, and/or complement-independent properdin effects; (2) To characterize the contribution of properdin and of the alternative pathway to the interaction between platelets and leukocytes by using pathway- and effector-specific complement inhibitors in ex-vivo analyses of platelet/leukocyte aggregate and thrombi formation in human whole blood. Collectively, these studies will significantly advance the understanding of the functions of human properdin and the alternative pathway in the pathogenesis of vascular diseases by defining a new molecular mechanism for platelet/leukocyte interactions. In addition, by identifying candidate inhibitors of properdin functions, this study will allow the design of unique therapeutic strategies to modulate the interaction between platelet and leukocytes for treating cardiovascular diseases where complement, platelet/leukocyte aggregates, and thrombi play key roles in the pathogenesis.

描述（由申请人提供）：在美国，心血管疾病是男女死亡的主要原因。炎症性心血管疾病患者循环中活化血小板和血小板/白细胞聚集体数量增加，这两者在疾病的发生和进展中起着核心作用。活化血小板促进 补体系统在其表面的启动和增殖，导致血管炎症和血栓形成。我们最近报道了一种分子机制，其中备解素，补体旁路途径的正调节剂，直接结合到激活的，但不静息血小板，独立于C3 b，并启动补体激活。我们的新的初步数据表明，离体人备解素增加血小板/白细胞聚集体的形成和发展的胶原诱导的血栓在全血中受到剪切应力。抑制备解素与C3 b和细胞的结合显著降低了这两种结果。备解素如何刺激血小板和白细胞之间的相互作用的机制是未知的，本提案的目的是定义这些机制。备解素主要由活化的白细胞产生。在炎症微环境中，活化的白细胞和血小板直接相互作用，并且白细胞衍生的备解素将以高浓度被血小板利用。我们假设备解素通过补体旁路途径依赖性机制（至少部分包括备解素启动的补体激活）以及通过不依赖于补体激活的机制（即充当细胞之间的桥梁）增强血小板和白细胞之间的相互作用。（1）确定备解素与C3 b以及与血小板和白细胞的相互作用如何被抑制，以防止在这些细胞上备解素介导的转化酶稳定或备解素引发的补体激活和/或非补体依赖性备解素效应;（2）通过在血小板/白细胞的离体分析中使用途径和效应子特异性补体抑制剂来表征备解素和旁路途径对血小板和白细胞之间相互作用的贡献。人全血中白细胞聚集和血栓形成。总的来说，这些研究将显着推进人类备解素的功能和替代途径的血管疾病的发病机制，通过定义一个新的分子机制，血小板/白细胞相互作用的理解。此外，通过鉴定备解素功能的候选抑制剂，本研究将允许设计独特的治疗策略来调节血小板和白细胞之间的相互作用，用于治疗补体、血小板/白细胞聚集体和血栓在发病机制中起关键作用的心血管疾病。