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: 10548134
• 负责人: Tomas M Mustelin
• 金额: $ 38.83万
• 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/10548134
• 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; 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; 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.

项目摘要/摘要 尽管有几种新的治疗选择，许多类风湿关节炎（RA）仍在继续 患有控制疾病不良。为了迫切需要发展更好的发展 疗法，支撑RA发病机理的分子机制需要更好 理解。最新的假设假设异常柠檬酸蛋白变成 `neo'-抗原和斯托克直接自身免疫，反对这种修改后的自我。现在的关键问题 RA患者的原因和/或异常发生过度和/或异常。 这里提出的研究将提供有关病理柠檬酸如何的新见解 发生在RA患者中。这项工作将有助于阐明分子机制 柠檬化酶PAD2和/或PAD4在触发RA时作用。反过来，这将是无价的 将其评估为药物靶标，并将提供生物标志物的机会来监视 该疾病的活性，可能将RA患者分为不同的亚群 需要不同的疗法。具体目的是： AIM 1。RA患者增加柠檬化的机制。 AIM 2。PAD4在氧化爆发调节中的新功能。 第一个目的直接在患者样本中寻求证据的证据 病理柠檬化以确定哪些在体内运行。他们的贡献 单独或组合蛋白质的蛋白质柠檬酸，与疾病相关的底物， 将研究包括与RA发病机理相关的底物混合物和细胞。 第二个目的探讨了PAD4和胞质之间的新颖链接的发现 人类嗜中性粒细胞中NADPH氧化酶机械（NOX2）的成分。柠檬酸 NOX2组件的组件可能通过阻止保护性而导致RA的发病机理 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鞭打和功能后果 这些位点在测试的氧化爆发反应上，因为据报道该响应是 参与自身免疫性。