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: 9252494
• 负责人: Viviana P Ferreira
• 金额: $ 37.88万
• 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/9252494
• 关键词: Address; Alternative Complement Pathway; Binding; Biological; 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; Complement Stabilization; Country; Data; Deposition; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Generations; Hemostatic function; Human; In Situ; Individual; Inflammatory; Injury; Knockout Mice; Lead; Length; Leukocytes; Ligands; Liquid substance; Mediating; Molecular; Molecular Biology Techniques; Monoclonal Antibodies; Mus; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Peptides; Phase; Physiological; Play; Properdin; Recombinants; Regulation; Reporting; Rest; Role; Site; Surface; Surface Plasmon Resonance; Therapeutic; Thrombosis; Thrombus; Tissues; Vascular Diseases; Vitronectin; Whole Blood; Woman; base; complement system; design; in vivo; inhibitor/antagonist; intravital microscopy; men; mortality; mutant; neutrophil; novel; prevent; public health relevance; 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，心血管疾病是男性和女性死亡的主要原因。炎症性心血管疾病患者循环活化血小板和血小板/白细胞聚集数量增加，这两者在疾病的发生和进展中都起着核心作用。活化血小板促进