Role of protein citrullination in rheumatoid arthritis

蛋白质瓜氨酸化在类风湿性关节炎中的作用

• 批准号: 10318576
• 负责人: Tomas M Mustelin
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318576
• 关键词: Address; Affect; Alleles; Antibodies; Applications Grants; Arginine; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Biological; Biological Markers; Biology; Cells; Data; Development; Disease; Drug Targeting; Enzymes; Genetic; Head; Human; Individual; Infection; Link; Malignant Neoplasms; Molecular; Monitor; NADPH Oxidase; Natural Immunity; PRTN3 gene; Pathogenesis; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Predisposition; Protein-arginine deiminase; Proteins; Publishing; Reaction; Regulation; Reporting; Research; Respiratory Burst; Rheumatoid Arthritis; Role; Sampling; Site; Sjogren' s Syndrome; Specificity; Surface; Sushi Domain; Synovial joint; Systemic Lupus Erythematosus; Testing; Therapeutic; Work; adaptive immunity; base; citrullinated protein; cyclic citrullinated peptide; gain of function; in vivo; inhibitor; insight; interest; neutrophil; novel; response; small molecule; systemic autoimmune disease; targeted treatment

Project Summary/Abstract Despite several new treatment options, many patients with rheumatoid arthritis (RA) continue to suffer from poorly controlled disease. To enable the urgently needed development of better therapies, the molecular mechanisms that underpin the pathogenesis of RA need to be better understood. The newest hypothesis postulates that abnormally citrullinated proteins become `neo'-self-antigens and stoke direct autoimmunity against this modified self. Key questions now are why and how excessive and/or abnormal citrullination occurs in RA patients. The research proposed here will provide novel insights into how pathological citrullination occurs in RA patients. This work will help elucidate the molecular mechanisms by which the citrullinating enzymes PAD2 and/or PAD4 act in triggering RA. This will, in turn, be invaluable for evaluating them as drug targets, and will provide biomarker opportunities to monitor the activity of the disease and possibly stratify RA patients into different subpopulations that may require different therapies. The Specific Aims are: AIM 1. The mechanism(s) of increased citrullination in RA patients. AIM 2. A novel function of PAD4 in oxidative burst regulation. The first Aim directly seeks evidence in patient samples of the five proposed mechanisms of pathological citrullination to determine which are operational in vivo. Their contributions individually, or in combinations, to protein citrullination of disease-relevant substrates, including substrate mixtures and cells relevant to RA pathogenesis will be investigated. The second Aim explores the discovery of a novel link between PAD4 and the cytosolic components of the NADPH oxidase machinery (NOX2) in human neutrophils. The citrullination of NOX2 components may contribute to the pathogenesis of RA by blocking a protective oxidative burst response. The molecular details of PAD4 interaction with NOX2 will be examined and the citrullination of specific arginine residues and the functional consequences of these sites on the oxidative burst response tested, as this response has been reported to be involved in tempering autoimmunity.

项目概要/摘要 尽管有几种新的治疗选择，许多类风湿性关节炎 (RA) 患者仍继续接受治疗 患有控制不良的疾病。为了更好地实现迫切需要的发展 治疗方面，支持 RA 发病机制的分子机制需要更好 明白了。最新的假设假设异常瓜氨酸化的蛋白质变成 “新”自身抗原并激发针对这种改变的自我的直接自身免疫。现在的关键问题 这是 RA 患者发生过度和/或异常瓜氨酸化的原因和方式。 这里提出的研究将为病理性瓜氨酸化如何提供新的见解 发生于 RA 患者。这项工作将有助于阐明其分子机制 瓜氨酸酶 PAD2 和/或 PAD4 可以触发 RA。反过来，这将是无价的 评估它们作为药物靶点，并将提供生物标志物机会来监测 疾病的活动性并可能将 RA 患者分为不同的亚群，这些亚群可能 需要不同的治疗方法。具体目标是： 目的 1. RA 患者瓜氨酸化增加的机制。 目的 2. PAD4 在氧化爆发调节中的新功能。 第一个目标直接在患者样本中寻找五种拟议机制的证据 病理瓜氨酸化以确定哪些在体内起作用。他们的贡献 单独或组合地对疾病相关底物进行蛋白质瓜氨酸化， 包括与 RA 发病机制相关的底物混合物和细胞将被研究。 第二个目标探索发现 PAD4 和胞质之间的新联系 人类中性粒细胞中 NADPH 氧化酶机制 (NOX2) 的组成部分。瓜氨酸化 NOX2 成分可能通过阻断保护性机制而促进 RA 的发病机制 氧化爆发反应。 PAD4 与 NOX2 相互作用的分子细节将是 检查和特定精氨酸残基的瓜氨酸化及其功能后果 这些位点对氧化爆发反应进行了测试，因为据报道这种反应是 参与调节自身免疫。