Polymorphisms of Antiphospholipid Protein Antigens

抗磷脂蛋白抗原的多态性

• 批准号: 6640492
• 负责人: JOAN T. MERRILL
• 金额: $ 39.23万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640492
• 关键词: anticoagulants; antiphospholipid syndrome; autoantibody; blood coagulation; blood proteins; gene expression; genetic polymorphism; human subject; pathologic process; patient oriented research; plasma; protein S; protein binding; protein protein interaction; recombinant proteins; systemic lupus erythematosus; thrombosis

DESCRIPTION (provided by applicant): The antiphospholipid syndrome (APS) is a life-threatening thrombotic disorder characterized by a spectrum of autoantibodies that interfere with blood clotting. Recent evidence suggests that minor genetic variations in coagulation proteins may affect the likelihood for thrombosis in APS patients, either by an indirect, additive risk, or by altering the function of target proteins in a way that affects autoantibody incidence or pathogenicity. This application proposes: Aim 1: To determine if combined, common variants of specific candidate genes associate with APS. A TDT analysis of 1,000 APS patients and their parents will be performed, examining strategic single nucleotide polymorphisms in three interacting coagulation proteins known to be implicated in APS pathology: 1.) the anticoagulant, protein S 2.) its plasma inhibitor, C4b Binding Protein (C4BP) 3.) beta 2-glycoprotein I, a major APS antigen which also may regulate protein S. Aim 2: To produce functional, recombinant protein S, beta 2-glycoprotein I and C4BP domains (both wild-type and polymorphic) in an insect cell system and to compare each in binding interactions with the others, and in their effects on protein S function in vitro. Aim 3: To evaluate individual APS plasma for the decreased free protein S which is known to be prevalent in these patients and to correlate this with presence or absence of candidate polymorphisms and with antibody specificities for the recombinant wild type or polymorphic domains. Single or combined genetic factors may determine the tertiary structures and strength of interactions between several, key protein targets of APS antibodies. Determining the impact of common polymorphisms on the occurrence and/or pathogenicity of autoantibodies could lead to improved diagnostic tests and/or novel, mechanism-based treatments for APS. Additionally, the study of differences in interactions between these coagulation proteins conferred by common, inherited polymorphisms will have intrinsic value, not limited to the antiphospholipid syndrome.

描述（由申请人提供）：抗磷脂综合征（AP）是 威胁生命的血小板疾病，其特征是 干扰血液凝结的自身抗体。最近的证据表明 凝血蛋白的较小遗传变异可能会影响可能性 通过间接，添加剂风险或通过 以影响自身抗体的方式改变靶蛋白的功能 发病率或致病性。本申请提出： 目标1：确定是否合并，特定候选基因的常见变体 与AP相关。对1,000名APS患者及其父母的TDT分析将 进行，检查三个战略单核苷酸多态性 相互作用的凝血蛋白已知与APS病理有关： 1.）抗凝蛋白S 2.）其血浆抑制剂C4B结合蛋白（C4BP） 3.）β2-糖蛋白I，一种主要的APS抗原，也可能调节蛋白质 s 目标2：生产功能性重组蛋白S，β2-糖蛋白I和 昆虫细胞系统中的C4BP结构域（野生型和多态性）以及 比较每种与其他人的绑定相互作用，及其对 蛋白质的体外功能。 目标3：评估降低的自由蛋白S的单个AP等离子体 已知在这些患者中普遍存在，并将其与存在相关 或缺乏候选多态性和具有抗体特异性 重组野生型或多态域。 单一或联合遗传因素可能决定第三级结构，并且 AP的几个关键蛋白质靶标之间的相互作用强度 抗体。确定常见多态性对发生的影响 自身抗体的致病性可能会改善诊断测试 和/或AP的基于机制的新颖，基于机制的治疗方法。此外，研究 这些凝血蛋白之间相互作用的差异由 常见的，遗传的多态性将具有内在价值，不限于 抗磷脂综合征。