SPORADIC MECHANISM OF THE ANTIPHOSPHOLIPID SYNDROME

抗磷脂综合征的散发机制

• 批准号: 6551707
• 负责人: JOAN T. MERRILL
• 金额: $ 18.08万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-15 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6551707
• 关键词: anticoagulants; apolipoproteins; autoantibody; autoimmune disorder; binding proteins; binding sites; biomarker; blood coagulation disorders; clinical research; complement pathway; disease /disorder proneness /risk; epitope mapping; female; hormone receptor; hormone regulation /control mechanism; human subject; pathologic process; phospholipid inhibitor; pregnancy; protein S; protein protein interaction; receptor binding; sex hormones; site directed mutagenesis; systemic lupus erythematosus; thrombosis; women's health

DESCRIPTION: (Adapted from the applicant's abstract)-The APLS is an autoimmune disease of sporadic and unpredictable thrombosis which leads to miscarriages, venous clots, strokes, and sudden death of young people. The only clinical tests available are nonspecific screening assays which detect a lupus anticoagulant or antiphospholipid autoantibodies, but do not predict which patients will develop life- threatening disease. Because of this, patients do not receive anticoagulant therapy until after a serious thrombotic event occurs. Then they are left on potentially dangerous anticoagulant regimens for life, with no assurance that they need it. There is an obvious mandate for better predictive testing and for more specific therapies aimed at the underlying coagulation disorder in this syndrome. A critical aspect of the problem that must be addressed by a disease model is the sporadic nature of the thrombotic events that occur. This application will evaluate a likely model for sporadic thrombosis, transient functional deficiency of the anticoagulant protein S. Functional protein S deficiency results from excessive binding by a protein S inhibitor, the C4BP, a dual regulator of the complement and coagulation systems. Functional inhibition of protein S by C4BP has been recently found in patients with APLS by many authors and is temporally related to clotting events. The applicants determined that beta2-GPI, the major target antigen for antiphospholipid autoantibodies, binds protein S and reverses inhibition of protein S by C4BP. A monoclonal anti-beta2-GPI antibody inhibits its interaction with protein S and causes functional protein S deficiency in vitro. The applicants hypothesize that a subset of pathogenic antiphospholipid autoantibodies inhibit interaction between beta2-GPI and protein S, causing intermittent thrombosis during states of high complement activity and excess C4BP, such as are found during lupus flare and pregnancy. The applicants propose to define interactions between protein S, beta2- GPI, and C4BP on a molecular level. Beta2-GPI and C4BP share homologous regions associated with the complement control protein superfamily. These are likely protein S-binding sites and will be targeted in mutagenesis experiments aimed at finding epitopes to which pathogenic antibodies bind. Peptides derived from the protein S-binding region of beta2-GPI might serve as antigens for a more specific clinical assay for pathogenic antiphospholipid autoantibodies or as a basis for a novel therapeutic agent. They will also evaluate the significance of the sex hormone-binding globulin (SHBG) region on protein S. Pregnancy is a risk factor for thrombosis in APLS, and decrease in protein S function is associated with oral contraceptive use. Therefore, possible modulation by sex-hormones of interactions between these proteins will be addressed in this application.

描述：（从申请人的摘要中进行了改编） - APLS是 散发性和不可预测的血栓形成的自身免疫性疾病 流产，静脉凝块，中风和年轻人突然死亡 人们。唯一可用的临床测试是非特异性筛查 检测狼疮抗凝剂或抗磷脂的测定 自身抗体，但不能预测哪些患者会发展生命 - 威胁性疾病。因此，患者没有接受 抗凝治疗直到发生严重的血栓形成事件后。 然后，将它们放在潜在危险的抗凝剂方案上 生活，不保证他们需要它。有一个明显的任务 进行更好的预测性测试和针对的更具体的疗法 该综合征的潜在凝血障碍。一个关键方面 疾病模型必须解决的问题是零星 发生的血栓形成事件的性质。 该应用将评估可能偶发性血栓形成的模型， 抗凝蛋白S的瞬时功能缺乏。 功能蛋白的缺乏症是由A的过度结合而导致的 蛋白质抑制剂，C4BP，补体的双调节剂 凝血系统。 C4BP对蛋白质的功能抑制已有 最近在许多作者的APL患者中发现，并且是时间的 与凝结事件有关​​。申请人确定beta2-gpi， 抗磷脂自身抗体的主要靶抗原结合 蛋白质S和C4BP对蛋白质的抑制作用。单克隆 抗BETA2-GPI抗体抑制其与蛋白质S和 导致功能蛋白在体外缺乏。申请人 假设一部分致病性抗磷脂自身抗体 抑制β2-GPI与蛋白质之间的相互作用，导致 高补体活性状态期间的间歇性血栓形成和 过量的C4BP，例如在狼疮和怀孕期间发现的。 申请人建议定义蛋白质S，beta2-之间的相互作用 GPI和C4BP分子水平。 beta2-GPI和C4BP共享同源 与补体控制蛋白超家族相关的区域。 这些可能是蛋白质S结合位点，将被针对 诱变实验旨在寻找表现到哪种病原体 抗体结合。从蛋白质S结合区域衍生的肽 Beta2-GPI可能是更具体的临床测定法的抗原 致病性抗磷脂自身抗体或作为新颖的基础 治疗剂。他们还将评估性别的重要性 蛋白质的激素结合球蛋白（SHBG）区域。怀孕是一种风险 APL中血栓形成的因素，蛋白质S功能的降低为 与口服避孕药使用相关。因此，可能的调制 通过这些蛋白质之间相互作用的性激素将被解决 在此应用程序中。