Investigation of Beta2-glycoprotein I Complexes in Antiphospholipid Syndrome

Beta2-糖蛋白 I 复合物在抗磷脂综合征中的研究

• 批准号: 8106003
• 负责人: Natalia Beglova
• 金额: $ 43.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-07 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8106003
• 关键词: Antibodies; Antigens; Antiphospholipid Syndrome; Autoimmune Diseases; Autoimmune Process; Binding; Biochemical; Biological Assay; Cell surface; Cells; Complex; Development; Docking; Drug Delivery Systems; Effectiveness; Endothelial Cells; Evaluation; Goals; In Vitro; Investigation; Lasers; Lead; Life; Lipoprotein Receptor; Measurement; Molecular; Mus; Mutation; NMR Spectroscopy; Pathologic; Patients; Pharmaceutical Preparations; Phospholipids; Plasma; Pregnancy loss; Property; Recurrence; Research; Role; Site-Directed Mutagenesis; Solutions; Surface; Syndrome; Thrombosis; Thrombus; base; beta 2-glycoprotein I; design; fetal; in vivo; inhibitor/antagonist; insight; mouse model; novel; novel strategies; prevent; protein structure; prototype; receptor; tool

DESCRIPTION (provided by applicant): Antiphospholipid syndrome (APS) is an autoimmune disease characterized clinically by thrombosis and/or recurrent fetal loss. Beta2-glycoprotein I (¿2GPI) is the major antigen for the antibodies associated with APS. Only the dimeric form of 2GPI generated by anti-2GPI antibodies is pathologically important, in contrast to monomeric 2GPI which is abundant in plasma. The primary hypothesis of the proposed study is that the interaction of 2GPI/anti-2GPI antibody complexes with lipoprotein receptors and anionic phospholipid is a potential drug target for interfering with thrombosis in APS. We created a dimeric inhibitor to selectively target dimeric 2GPI in 2GPI/anti-2GPI antibody complexes. This inhibitor disrupts the binding of 2GPI/antibody complexes with lipoprotein receptors and anionic phospholipid. The proposed studies will optimize the inhibitor that blocks the interaction of 2GPI/anti-2GPI antibody complexes with lipoprotein receptors and anionic phospholipid; use the inhibitor, site-directed mutagenesis, and functional studies in cells and in vivo to dissect the contribution of lipoprotein receptors and anionic phospholipid to thrombosis in APS. The studies will employ biophysical measurements of domain interactions, NMR and crystallographic determination of protein structures, cell-based assays and laser-induced thrombosis in live mice in pursuit of these goals. PUBLIC HEALTH RELEVANCE: Beta2-glycoprotein I (¿2GPI) is the major antigen for the antibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. APS patients with thrombosis are treated chronically with general antithrombotic medications which are not always effective. We will use in vivo mouse model in combination with biochemical and biophysical studies to understand how 2GPI/anti-2GPI antibody complexes interact with cellular receptors leading to thrombosis in APS. The insights gained from the study could be used as a basis for new treatments for people suffering from APS.

描述（由申请人提供）：抗磷脂综合征（APS）是一种自身免疫性疾病，临床特征为血栓形成和/或复发性胎儿丢失。β 2-糖蛋白I（<$2GPI）是与APS相关的抗体的主要抗原。与血浆中丰富的单体2GPI相反，只有由抗2GPI抗体产生的2GPI的二聚体形式在病理学上是重要的。该研究的主要假设是2GPI/抗2GPI抗体复合物与脂蛋白受体和阴离子磷脂的相互作用是干扰APS中血栓形成的潜在药物靶点。我们创建了二聚体抑制剂以选择性地靶向2GPI/抗2GPI抗体复合物中的二聚体2GPI。该抑制剂破坏2GPI/抗体复合物与脂蛋白受体和阴离子磷脂的结合。拟开展的研究将优化阻断2GPI/抗2GPI抗体复合物与脂蛋白受体和阴离子磷脂相互作用的抑制剂;使用该抑制剂、定点突变和细胞及体内功能研究，剖析脂蛋白受体和阴离子磷脂对APS血栓形成的作用。这些研究将采用域相互作用的生物物理测量、蛋白质结构的NMR和晶体学测定、基于细胞的测定和激光诱导的活小鼠血栓形成来实现这些目标。 公共卫生相关性：β 2-糖蛋白I（2GPI）是抗磷脂综合征（APS）相关抗体的主要抗原，APS是一种以血栓形成和反复流产为特征的自身免疫性疾病。患有血栓形成的APS患者长期接受一般抗血栓药物治疗，但这些药物并不总是有效。我们将使用体内小鼠模型结合生物化学和生物物理学研究，以了解2GPI/抗2GPI抗体复合物如何与细胞受体相互作用，导致APS血栓形成。从这项研究中获得的见解可以作为APS患者新疗法的基础。