ANTI-PHOSPHOLIPID ANTIBODIES AND THE PROTEIN C SYSTEM

描述（由申请方提供）：狼疮抗凝剂（LA）和 抗磷脂抗体（APA）与以下疾病的风险增加有关 血栓形成我们假设阿帕和/或LA亚组导致 通过蛋白C抗凝剂的选择性抑制血栓形成 通路我们已经发现，活化蛋白的膜需求 C（APC）复合物与促凝复合物的性质不同。 具体地，APC复合物需要磷脂酰乙醇胺（PE）用于 活动最近，我们还观察到磷脂氧化增强了 APC活动具体这些要求模仿了至少一个 血栓形成狼疮患者中发现的自身抗体亚群 APC复合物的选择性抑制，因此可以提供 特异性以及APC途径、LA/APAs和血栓形成之间的联系。是 此应用程序的目标是确定 促凝剂的不同膜结构要求， 抗凝复合物和病原抗体的特异性， 强调氧化作用。我们将确定 血栓前抗体（Abs）对APC复合物的抑制， 磷脂需求（PE的存在;氧化的作用）， 抗体（蛋白质;膜;蛋白质/膜）和其他可能作用 辅因子蛋白嵌合形式的APC用于鉴定 血栓前抗体和抗体对蛋白C的其他成员的流行 途径，TM和EPCR也将进行研究。欣赏分子 蛋白C通路的选择性抑制机制， LA/APA的可识别亚组应能更好地预测和 监测测试和潜在的更具体和更安全的治疗，在这些 很难管理病人。

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.