Structural Studies of Beta-2 glycoprotein I in the Antiphospholipid Syndrome

抗磷脂综合征中 Beta-2 糖蛋白 I 的结构研究

• 批准号: 10561597
• 负责人: Nicola Pozzi
• 金额: $ 38.86万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10561597
• 关键词: Address; Affect; Age; Antibodies; Anticoagulants; Antigens; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Architecture; Area; Arteries; Attention; Autoantibodies; Autoimmune; Autoimmune Diseases; Binding; Biology; Blood; Blood Platelets; Blood Vessels; Blood coagulation; Chemicals; Clinical; Coagulation Process; Complex; Computer Simulation; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Reagent Kits; Diagnostic tests; Disease; Engineering; Fluorescence Resonance Energy Transfer; General Population; Glycoproteins; Goals; Health; Healthcare Systems; Hemorrhage; Human; Immobilization; Immunoassay; Individual; Intervention; Investigation; Knowledge; Laboratories; Learning; Life; Life Style; Ligands; Link; Low-Molecular-Weight Heparin; Mammalian Cell; Medicine; Molecular; Molecular Conformation; Myocardial Infarction; Oxidation-Reduction; Oxidoreductase; Pathogenicity; Pathologic; Patients; Performance; Pharmaceutical Preparations; Physicians; Physiological; Physiology; Plasma; Pregnancy Complications; Primary Care; Property; Protein Disulfide Isomerase; Protein Engineering; Protein Glycosylation; Pulmonary Embolism; Recombinants; Recurrence; Regimen; Reproducibility; Research Project Grants; Risk; Risk Factors; Roentgen Rays; Role; Scientist; Side; Signal Pathway; Site-Directed Mutagenesis; Societies; Spectrum Analysis; Standardization; Stroke; Structure; Surface; System; Testing; Therapeutic; Thrombophilia; Thrombosis; Time; Uncertainty; Vascular System; Veins; Venous Thrombosis; Visualization; Work; X-Ray Crystallography; beta 2-glycoprotein I; biophysical analysis; clinical investigation; conformational conversion; cost; data exchange; design; detection test; disability; disulfide bond; follow-up; high risk; immunogenic; immunogenicity; improved; information gathering; innovation; negative affect; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; obstetrical complication; pathogenic autoantibodies; patient population; pharmacologic; prevent; prophylactic; protein purification; rational design; side effect; single molecule; structural biology; structural determinants; thrombotic; urgent care

Project Summary/Abstract Beta-2 glycoprotein-I (b2GPI) is a 50-kDa glycoprotein that circulates in the blood at a concentration of 0.2 mg/ml. It was originally discovered in 1961 but received little attention until 1990 when it was identified as the dominant antigen of antiphospholipid antibodies (aPL) in the autoimmune disorder known as Antiphospholipid Syndrome (APS). Patients affected by APS develop blood clots in veins and arteries as well as pregnancy complications. Occlusions of the vascular system may lead to life-threatening complications such as myocardial infarction, pulmonary embolism and stroke. Despite the established correlation between the presence of anti-b2GPI antibodies and thrombosis, APS remains incredibly challenging to diagnose and treat for physicians. There are two main issues. First, anti-b2GPI antibodies are very heterogeneous, and not all of them are pathogenic. Hence, laboratory tests are difficult to develop, standardize and interpret. This affects our ability to identify, with confidence, patients at higher risk for thrombosis who require prompt pharmacological intervention. Second, treatment options are limited to the prophylactic administration of long-term anticoagulants, anti-platelets, and low molecular weight heparin, that block the downstream effect of aPL, i.e., activation of the clotting cascade. This mechanism of action, however, is non-optimal for treating APS patients and, in addition to negatively affecting patients’ lifestyle and exposing them to the risk of fatal bleeding, among other things, these drugs also fail to prevent thrombotic recurrences in ~30% of the APS patient population, especially in those individuals with arterial thrombosis. To address these unmet clinical needs, physician and basic scientists have joined forces over the past twenty years and launched several key initiatives with the goal of standardizing the diagnosis of APS patients and determining the optimal management of aPL-positive patients. Thus, understanding the role of b2GPI in APS became a top priority in the field. Thanks to these collective efforts, much has been learned about the subclasses of aPL causing thrombosis and the signaling pathways triggered by anti-β2GPI antibodies. Less clear, however, remain the structural properties of β2GPI, the mechanisms controlling antigen-antibody recognition and the circumstances under which β2GPI becomes immunogenic. To bridge this gap in our fundamental knowledge, this research project seeks to elucidate the structural architecture β2GPI under conditions relevant to physiology, define the structural determinants for the interaction of β2GPI with aPL and physiological ligands, and develop an improved diagnostic test for the detection of pathogenic anti-b2GPI antibodies in patients’ plasma. Information gathered through these studies will contribute to establishing the missing link between structure, function, and immunogenicity of β2GPI in APS, and will open new avenues for APS-specific diagnostics and therapeutics.

项目总结/摘要 β-2糖蛋白-I（b2 GPI）是一种50 kDa的糖蛋白，在血液中以0.2 mg/ml。它最初于1961年被发现，但直到1990年才被确定为 抗磷脂抗体（aPL）的显性抗原在自身免疫性疾病中被称为 抗磷脂综合征（APS）。受APS影响的患者也会在静脉和动脉中形成血栓 怀孕并发症。血管系统的闭塞可能导致危及生命的并发症， 如心肌梗塞、肺栓塞和中风。尽管已经确定了 由于存在抗b2 GPI抗体和血栓形成，APS的诊断仍然非常具有挑战性， 为医生治疗。有两个主要问题。首先，抗b2 GPI抗体是非常异质性的，并且不 都是致病的因此，实验室测试很难开发，标准化和解释。这影响 我们有能力自信地识别出血栓形成风险较高、需要及时药物治疗的患者， 干预其次，治疗选择仅限于预防性给予长期抗凝剂， 抗血小板和低分子量肝素，它们阻断aPL的下游效应，即，激活 凝血级联反应然而，这种作用机制对于治疗APS患者来说不是最佳的，并且， 对患者的生活方式产生负面影响，并使他们面临致命出血的风险，除其他外， 药物也不能预防约30%的APS患者的血栓复发，尤其是那些 患有动脉血栓的人。为了解决这些未满足的临床需求，医生和基础科学家已经 在过去的二十年里，联合起来，发起了几项关键倡议，目标是标准化 APS患者的诊断和确定APL阳性患者的最佳管理。因此，在本发明中， 了解b2 GPI在APS中的作用成为该领域的首要任务。由于这些集体努力， 关于引起血栓形成的aPL亚类和触发血栓形成的信号通路， 抗β2GPI抗体。然而，尚不清楚β2GPI的结构特性， 控制抗原-抗体识别和β2GPI成为免疫原性的情况。到 弥合我们基础知识的这一差距，本研究项目旨在阐明结构 结构β2GPI在相关的生理条件下，定义结构决定因素， 研究β2GPI与aPL和生理配体的相互作用，并开发一种改进的诊断试验， 检测患者血浆中的病原性抗b2 GPI抗体。通过这些收集的信息 研究将有助于建立β2GPI的结构、功能和免疫原性之间缺失的联系 这将为APS特异性诊断和治疗开辟新的途径。