Role of protein citrullination in rheumatoid arthritis

项目摘要/摘要 尽管有几种新的治疗选择，许多类风湿性关节炎(RA)患者仍在继续 患上控制不好的疾病。使急需发展的更好 治疗，支持RA发病机制的分子机制需要更好地 明白了。最新的假说认为，异常的瓜氨酸化蛋白质 ‘neo’--自身抗原，并激发针对这种修饰的自我的直接自身免疫。现在的关键问题 类风湿关节炎患者发生瓜氨酸化过度和/或异常的原因和方式。 这里提出的研究将为病理性瓜氨酸化提供新的见解 发生于类风湿性关节炎患者。这项工作将有助于阐明 瓜氨酸酶PAD2和/或PAD4在触发类风湿关节炎中起作用。反过来，这将是无价的。 用于评估它们作为药物靶标，并将提供生物标记物机会来监测 疾病的活动性，并可能将RA患者分成不同的亚群，可能 需要不同的治疗方法。具体目标是： 目的1.类风湿关节炎患者瓜氨酸氨基转移酶升高的机制(S)。 目的2.PAD4在氧化猝发调节中的新功能。 第一个目标是直接在患者样本中寻找五种拟议机制的证据 病理性瓜氨酸化以确定哪些是在体内可操作的。他们的贡献 单独或组合，以蛋白与疾病相关的底物的瓜氨酸化， 包括底物混合物和与RA发病相关的细胞。 第二个目标是探索发现PAD4和胞浆之间的新联系 人类中性粒细胞中NADPH氧化酶机械(NOX2)的组成。瓜氨酸化 可能通过阻断保护性的NOX2组分参与RA的发病 氧化猝发反应。PAD4与NOX2相互作用的分子细节如下 研究了特定精氨酸残基的瓜氨酸化及其功能后果 这些部位对氧化猝发反应进行了测试，因为有报道称这种反应是 与锻炼自身免疫力有关。

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.