ANTI-PHOSPHOLIPID ANTIBODIES AND THE PROTEIN C SYSTEM

抗磷脂抗体和蛋白 C 系统

• 批准号: 6606197
• 负责人: NAOMI L ESMON
• 金额: $ 29.88万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6606197
• 关键词: antiphospholipid syndrome; autoantibody; blood banks; blood coagulation; chimeric proteins; clinical research; fibrinolysis; human subject; human tissue; patient /disease registry; protein C; prothrombin; systemic lupus erythematosus; thrombosis

DESCRIPTION (provided by the applicant): Lupus anticoagulants (LAs) and anti-phospholipid antibodies (APAs) are associated with an increased risk of thrombosis. It is our hypothesis that APA and/or LA subgroup(s) lead to thrombosis through the selective inhibition of the protein C anticoagulant pathway. We have found that the membrane requirements of the activated protein C (APC) complex are different from those of the procoagulant complexes. Specifically, the APC complex requires phosphatidylethanolamine (PE) for activity. Recently, we have also observed that phospholipid oxidation enhances APC activity specifically. These requirements mimic those of at least a subpopulation of autoantibodies found in lupus patients with thrombosis for the selective inhibition of the APC complex and thus may provide both the specificity and the link between the APC pathway, LA/APAs and thrombosis. It is the goal of this application to determine the relationship between the differential membrane structure requirements of the procoagulant and anticoagulant complexes and the specificity of pathogenic antibodies with emphasis on the role of oxidation. We will determine the mechanism of inhibition of the APC complex by prothrombotic antibodies (Abs) in terms of phospholipid requirements (presence of PE; role of oxidation), the target of the Abs (protein; membrane; protein/membrane) and possible role of other cofactor proteins. The utility of a chimeric form of APC to identify prothrombotic Abs and the prevalence of Abs to other members of the protein C pathway, TM and EPCR will also be investigated. Appreciation of the molecular mechanisms involved in the selective inhibition of the protein C pathway by identifiable subgroup(s) of LA/APAs should lead to better predictive and monitoring tests and potentially more specific and safer therapies in these difficult to manage patients.

描述（由申请人提供）：狼疮抗凝剂（LAS）和 抗磷脂抗体（APA）与增加的风险有关 血栓形成。我们的假设是APA和/或LA亚组导致 通过选择性抑制蛋白C抗凝剂的选择性抑制 路径。我们发现活化蛋白的膜需求 C（APC）复合物不同于Procagulant复合物的复合物。 具体而言，APC复合物需要磷脂酰乙醇胺（PE）才 活动。最近，我们还观察到磷脂氧化增强了 APC活动专门。这些要求至少模仿 在血栓形成的狼疮患者中发现的自身抗体的亚群 选择性抑制APC复合物，因此可以同时提供 特异性和APC途径，LA/APA和血栓形成之间的联系。这是 该应用程序的目的是确定 Procagulant的差异膜结构要求和 抗凝剂复合物和致病抗体的特异性 强调氧化作用。我们将确定 促孕抗体抗体（ABS）抑制APC复合物 磷脂要求（PE的存在；氧化作用），是 ABS（蛋白质；膜；蛋白质/膜）和其他可能的作用 辅因子蛋白。 APC的嵌合形式的效用 促血栓形成ABS和ABS的患病率向其他蛋白质C的其他成员流行 途径，TM和EPCR也将进行研究。分子的欣赏 通过选择性抑制蛋白C途径的机制 LA/APA的可识别子组应带来更好的预测性和 监测测试以及可能更具体，更安全的疗法 难以管理患者。