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.

项目概要/摘要 Beta-2 糖蛋白-I (b2GPI) 是一种 50 kDa 的糖蛋白，在血液中以 0.2 浓度消除 mg/ml，最初于 1961 年被发现，但直到 1990 年才被确定为 自身免疫性疾病中抗磷脂抗体 (aPL) 的抗原 抗磷脂综合征 (APS)。受 APS 影响的患者也会在静脉和动脉中出现血栓。 如妊娠并发症，血管系统闭塞可能会导致危及生命的并发症。 尽管心肌梗塞、肺栓塞和中风之间存在相关性。 由于存在抗 b2GPI 抗体和血栓形成，APS 的诊断和诊断仍然具有极大的挑战性 对于医生来说，存在两个主要问题：首先，抗 b2GPI 抗体非常异质，而且不均匀。 所有这些都是致病性的，因此实验室检测很难开发、标准化和解释。 我们有能力自信地识别出血栓形成风险较高且需要及时药物治疗的患者 其次，治疗选择仅限于预防性服用长期抗凝剂。 抗血小板和低分子量肝素，可阻断 aPL 的下游效应，即激活 然而，这种作用机制对于治疗 APS 患者来说并不是最佳的。 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，其中包括 也无法预防大约 30% 的 APS 患者群体中血栓药物的复发，尤其是那些 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，各方通力合作，发起了多项关键举措，旨在标准化 APS 患者的诊断并确定 aPL 阳性患者的最佳治疗方案。 由于这些集体努力，了解 b2GPI 在 APS 中的作用成为该领域的首要任务。 关于导致血栓形成的 aPL 亚类以及触发的信号通路，我们已经了解了很多 然而，β2GPI 的结构特性和机制尚不清楚。 控制抗原-抗体识别以及β2GPI变得具有免疫原性的环境。 为了弥合我们基础知识中的这一差距，该研究项目旨在阐明结构 在与生理学相关的条件下构建β2GPI，定义结构决定因素 β2GPI 与 aPL 和生理配体的相互作用，并开发一种改进的诊断测试 检测患者血浆中的致病性抗 b2GPI 抗体 通过这些信息收集的信息。 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 并将为 APS 特异性诊断和治疗开辟新途径。