ANTI-PHOSPHOLIPID ANTIBODIES AND THE PROTEIN C SYSTEM

抗磷脂抗体和蛋白 C 系统

基本信息

批准号：
6948912
负责人：
NAOMI L ESMON
金额：
$ 27.57万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
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/6948912
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

项目摘要

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（LA）和抗磷脂抗体（APA）与以下风险增加相关：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 抗凝剂形成血栓途径。我们发现活化蛋白的膜要求 C（APC）复合物与促凝血复合物不同。具体来说，APC 复合物需要磷脂酰乙醇胺 (PE) 活动。最近，我们还观察到磷脂氧化增强了特别是 APC 活动。这些要求至少模仿了在患有血栓的狼疮患者中发现的自身抗体亚群选择性抑制 APC 复合物，因此可以提供 APC 通路、LA/APA 和血栓形成之间的特异性和联系。这是该应用程序的目标是确定之间的关系促凝剂和膜结构的要求不同抗凝复合物和致病性抗体的特异性强调氧化作用。我们将确定机制促血栓抗体 (Abs) 对 APC 复合物的抑制作用磷脂需求（PE的存在；氧化作用），目标 Abs（蛋白质；膜；蛋白质/膜）以及其他可能的作用辅因子蛋白。 APC 嵌合形式在鉴定中的效用血栓前抗体和蛋白 C 其他成员抗体的流行率途径、TM 和 EPCR 也将被研究。分子鉴赏选择性抑制蛋白 C 通路的机制 LA/APA 的可识别亚组应能带来更好的预测和结果监测这些方面的测试以及可能更具体和更安全的治疗方法难以管理患者。