Causes and Roles of Hypercitrullination in Preclinical Rheumatoid Arthritis

项目摘要 风湿性关节炎（RA）影响多达1-2%的一般人群在北美。RA的病因是 但涉及基因和环境之间复杂的相互作用。随着更多 随着有效的RA治疗方法的出现，RA护理的重点正在从控制炎症转向早期治疗， 检测、预防和治疗这种疾病。本项目的最终目标是了解 RA的发病过程已经开始。这项研究的初步数据表明，从健康人中获得的血细胞， RA患者的一级亲属（FDR）已经显示出几种异常特征， 未经治疗的RA患者，表明这些异常特征早于RA的临床症状。第一 本项目的目的是利用生物化学方法来表征血细胞中的异常特征 并在这些特征之间建立时间顺序和因果关系。第二个目标是 使用药理学和遗传学方法来研究异常特征的级联是如何 以及一个特征如何导致下一个特征。最后的目的是检查从新生儿中获得的血细胞。 在治疗前后诊断的RA患者，以确定有效的RA治疗是否会减轻 这些异常的特征。总之，该项目将描绘一系列分子事件，导致 RA临床症状的发展，并将使我们更接近RA的初始触发因素。

Project Summary Rheumatoid arthritis (RA) affects up to 1-2% of the general population in North America. The cause of RA is still not fully understood but involves complicate interactions between genes and environment. As more effective therapies for RA are emerging, the focus of RA care is shifting from controlling inflammation to early detection, prevention, and cure of this disease. The ultimate goal of this project is to understand how the disease process of RA is initiated. Preliminary data of this study suggest that blood cells obtained from healthy first-degree relatives (FDRs) of RA patients already display several abnormal features that are also seen in untreated RA patients, indicating that those abnormal features predate the clinical symptoms of RA. The first aim of this project is to use biochemical approaches to characterize those abnormal features in blood cells from FDRs, and to establish a chronological and causal relationship among those features. The second aim is to use pharmacological and genetic approaches to examine how the cascade of the abnormal features is triggered and how one feature leads to the next. The final aim is to examining blood cells obtained from newly diagnosed RA patients before and after treatments in order to determine if effective RA treatment will mitigate these abnormal features. Taken together, this project will delineate a sequence of molecular events leading to the development of clinical symptoms of RA and will bring us one step closer to the initial trigger of RA.