Role of protein citrullination in rheumatoid arthritis

项目总结/摘要 尽管有几种新的治疗选择，但许多类风湿关节炎（RA）患者仍继续 患上控制不佳的疾病为了使迫切需要的发展更好地 治疗，支持RA发病机制的分子机制需要更好 明白最新的假说假定，异常瓜氨酸化的蛋白质 “新”自身抗原和斯托克直接针对这种修饰的自身的自身免疫。现在的关键问题 为什么以及如何在RA患者中发生过量和/或异常的瓜氨酸。 这里提出的研究将为病理性瓜氨酸酶如何 发生在RA患者身上。这项工作将有助于阐明的分子机制， 瓜氨酸酶PAD 2和/或PAD 4在触发RA中起作用。这反过来将是非常宝贵的 用于评估它们作为药物靶点，并将提供生物标志物的机会，以监测 活动的疾病，并可能分层RA患者到不同的亚群， 需要不同的疗法。具体目标是： AIM 1. RA患者中瓜氨酸增加的机制。 AIM 2. PAD 4在氧化爆发调节中的新功能。 第一个目的是直接在患者样本中寻找五种拟议机制的证据， 病理瓜氨酸酶，以确定哪些在体内起作用。其捐款 单独地或组合地与疾病相关底物的瓜氨酸蛋白结合， 包括基质混合物和与RA发病机制相关的细胞。 第二个目的是探索发现PAD 4和细胞溶质之间的新联系。 人中性粒细胞中NADPH氧化酶机制（NOX 2）的组成部分。的瓜氨酸化 NOX 2成分的减少可能通过阻断保护性的 氧化爆发反应PAD 4与NOX 2相互作用的分子细节将在下文中描述。 审查和瓜氨酸的具体精氨酸残基和功能的后果， 这些网站上的氧化爆发反应测试，因为这种反应已被报道， 参与调节自身免疫

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.