ANTI-PHOSPHOLIPID ANTIBODIES AND THE PROTEIN C SYSTEM

说明(申请人提供)：狼疮抗凝剂(LAS)和 抗磷脂抗体(APA)与糖尿病风险增加有关 血栓形成。我们的假设是APA和/或LA亚群(S)导致 选择性抑制蛋白C抗凝剂引起的血栓形成 路径。我们已经发现，膜所需的活化蛋白 C(APC)复合体不同于促凝剂复合体。 具体来说，APC复合体需要磷脂酰乙醇胺(PE)来 活动。最近，我们也观察到磷脂氧化增强 特别是APC活动。这些要求与至少一个 狼疮血栓形成患者自身抗体亚群的检测 选择性地抑制APC复合体，从而可以提供 APC通路、LA/APAs和血栓形成之间的特异性和联系。它是 此应用程序的目标是确定 促凝剂和促凝剂对膜结构的不同要求 抗凝血复合体及其致病抗体的特异性 强调氧化的作用。我们将确定其机制。 血栓前抗体对APC复合体的抑制作用 磷脂需求(PE的存在；氧化的作用)，目标 抗体(蛋白质；膜；蛋白质/膜)及其可能的作用 辅因子蛋白。嵌合形式的APC用于鉴定 血栓前抗体及其对蛋白C其他成员的流行率 途径、TM和EPCR也将被调查。对分子的鉴赏 蛋白C途径选择性抑制的机制 LA/APA的可识别亚群(S)应导致更好的预测性和 监测测试和潜在的更具体和更安全的治疗 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.