ROLE OF MICROPARTICLES IN THE ANTI-PHOSPHOLIPID SYNDROME

微粒在抗磷脂综合征中的作用

• 批准号: 8039944
• 负责人: KEITH MCCRAE
• 金额: $ 34.93万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8039944
• 关键词: ANXA2 gene; Accounting; Address; Alteplase; Annexins; Antibodies; Anticardiolipin Antibodies; Anticoagulant therapy; Anticoagulants; Antigenic Specificity; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Aspirin; Binding; Binding Proteins; Blood Platelets; Blood Vessels; CD36 gene; Cells; Clinical; Coagulation Process; Disease; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Event; Family; Generations; Goals; Heparin; Immunoglobulin G; In Vitro; Individual; Institution; Kinetics; Laboratories; Lupus Coagulation Inhibitor; Modeling; Mus; Pathogenesis; Pathway interactions; Patients; Phospholipids; Plasma; Protein C; Prothrombin; Recording of previous events; Recurrence; Reporting; Research Personnel; Role; Serological; Source; Specificity; Surface; Testing; Thrombophilia; Thromboplastin; Thrombosis; Thrombus; Venous Thrombosis; anti-endothelial cell antibody; beta 2-glycoprotein I; crosslink; fetal; in vivo; monocyte; neutrophil; oxidized low density lipoprotein; programs; response; translational study

Antiphospholipid antibodies (APLA) are associated with arterial and venous thrombosis, as well as recurrent fetal loss, and are the most common cause of acquired thrombophilia. In vitro studies have suggested several mechanisms that might account for the pathogenic effects of these antibodies. APLA comprise a heterogeneous family of antibodies, and rather than binding anionic phospholipid as originally proposed, react preferentially with phospholipid binding proteins such as beta2 glycoprotein I (beta2GPI), prothrombin, or oxidized phospholipids; of these, beta2GPI is the most common. Several groups, including our own, have reported that APLA bind to endothelial cells, and we have recently demonstrated that "APLA"/anti-beta2GPI antibodies induce endothelial cell activation by cross-linking annexin II through binding of annexin ll-bound beta2GPI and initiation of an activation pathway involving TLR-4 and NF-KB. Despite these mechanistic observations, however, there are no specific markers of the prothrombotic state in patients with APLA. Two reports have suggested that increased levels of procoagulant microparticles circulate in the plasma of these patients; however, the origin of these microparticles, their association with "APLA" of defined specificity (i.e. anti-beta2GPI, anti-oxidized LDL), or their correlation with thrombotic events have not been well delineated. In Specific Aim 1 of this application, we propose to compare the levels of circulating microparticles in 200 patients with APLA with those in 50 normal individuals. We will also determine the cellular origin of the circulating microparticles, and whether the number of microparticles or their cell of origin correlates with the serologic specificity of the "APLA". In Specific Aim 2, we will assess the correlation between the level of circulating microparticles and a clinical history of thrombosis, compare the procoagulant activity of microparticles from patients and controls, determine whether therapy of patients with "APLA" with aspirin and heparin reduces the level of microparticles, and evaluate the relationship between circulating microparticles and the ability of APLA to activate cells in vitro. In Specific Aim 3, we will assess the thrombogenicity of "APLA" in a mice, and determine the role of annexin II in thrombus formation. These clinical/translational studies should provide new information concerning the role of circulating microparticles in APLA-associated thrombosis, as well as the in vivo mechanisms of APLA in patients.

抗磷脂抗体 (APLA) 与动脉和静脉血栓形成以及复发性血栓相关 胎儿丢失，是获得性血栓形成倾向的最常见原因。体外研究表明 可能解释这些抗体致病作用的几种机制。 APLA 包括 异质抗体家族，而不是像最初提出的那样结合阴离子磷脂， 优先与磷脂结合蛋白发生反应，例如 beta2 糖蛋白 I (beta2GPI)、凝血酶原或 氧化磷脂；其中，beta2GPI 是最常见的。有几个团体，包括我们自己的团体， 报道称 APLA 与内皮细胞结合，我们最近证明“APLA”/抗 beta2GPI 抗体通过与膜联蛋白 II 结合交联膜联蛋白 II 来诱导内皮细胞活化 beta2GPI 以及涉及 TLR-4 和 NF-KB 的激活途径的启动。尽管有这些机械 然而，根据观察结果，APLA 患者的血栓前状态尚无特异性标志物。二 报告表明，这些人血浆中循环的促凝血微粒水平增加 患者;然而，这些微粒的起源，它们与具有明确特异性的“APLA”的关联（即 抗β2GPI、抗氧化LDL）或其与血栓事件的相关性尚未得到很好的描述。在 本应用的具体目标 1，我们建议比较 200 个国家/地区的循环微粒水平 APLA 患者与 50 名正常人的情况。我们还将确定细胞起源 循环微粒，以及微粒的数量或其来源细胞是否与 “APLA”的血清学特异性。在具体目标 2 中，我们将评估以下水平之间的相关性： 循环微粒和血栓形成的临床病史，比较以下物质的促凝血活性 来自患者和对照的微粒，确定是否用阿司匹林治疗“APLA”患者 和肝素降低微粒水平，并评估循环之间的关系 微粒和 APLA 在体外激活细胞的能力。在具体目标 3 中，我们将评估 小鼠中“APLA”的血栓形成性，并确定膜联蛋白 II 在血栓形成中的作用。这些 临床/转化研究应提供有关循环微粒作用的新信息 APLA 相关血栓形成以及 APLA 在患者体内的机制。