Causes and Roles of Hypercitrullination in Preclinical Rheumatoid Arthritis

项目摘要 在北美，类风湿性关节炎(RA)影响多达1%-2%的总人口。类风湿性关节炎的原因是 仍然没有完全了解，但涉及基因和环境之间复杂的相互作用。作为更多 治疗RA的有效方法正在涌现，RA护理的重点正从控制炎症转向早期 这种疾病的检测、预防和治疗。本项目的最终目标是了解 启动了类风湿关节炎的发病过程。这项研究的初步数据表明，从健康人群中获得的血细胞 RA患者的一级亲属(FDR)已经表现出几个异常特征，在 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 这个项目的目的是使用生化方法来表征血细胞中的异常特征。 并建立这些特征之间的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检查异常特征的级联是如何 以及一个特征如何通向下一个特征。最终的目标是检查从新获得的血细胞 在治疗前后诊断类风湿关节炎患者，以确定有效的类风湿关节炎治疗是否会缓解 这些反常的特征。综上所述，这个项目将描绘出一系列导致 RA临床症状的发展，将使我们离RA的初始触发更近一步。

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.