Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis

描述（由申请人提供）： 我们正在进入一个令人兴奋的儿科风湿病学时代。新的治疗方法正在改善青少年特发性关节炎（JIA）儿童的生活，以至于现在在我们的候诊室里很少看到轮椅或拐杖。即使是过去常用于治疗关节挛缩的夹板，也很少在我们的病人身上看到。 尽管我们取得了进展，但JIA的缓解是罕见的。我们的合作者Carol Wallace博士最近的工作表明，只有5%患有多关节JIA（该疾病最严重的形式）的儿童在诊断5年后病情得到缓解。我们实现缓解的部分问题是，在生物学水平上，我们并不真正理解什么是“缓解”。这是一个经典的例子，当你不知道你要去哪里的时候，很难到达某个地方。这份拨款申请是关于了解我们的目标。 在本申请中，我们的目标是使用基于微阵列的生物标志物更好地理解什么是“缓解”。来自Cobb（急性炎症）和Jarvis（慢性炎症）实验室的研究已经证明了使用全基因组表达谱的可行性，可以用于定义疾病“状态”（例如，感染与未感染;缓解或未缓解）。此外，Jarvis实验室已经证明了使用这些技术来预测临床结果的前景。对于每一组，这些有希望的初步研究必须使用更大的患者人群和前瞻性研究设计进行验证。 在本申请中，我们提出验证外周血生物标志物，这些生物标志物已经表明：（1）幼年型关节炎的缓解可以通过不同的基因表达标记在分子水平上鉴定;（2）这些标记包括促炎和抗炎基因网络的平衡;以及（3）可以基于外周血单核细胞中出现的分子标记来预测达到非活动性疾病状态的儿童的临床过程。此外，我们将通过开发基于PCR的全血测定法来确定缓解或临床结果的最稳健指标，从而向这项工作的临床应用迈出另一步。 该项目汇集了来自两个非常不同学科的两位经验丰富的研究人员：儿科风湿病学（贾维斯博士）和外科重症监护（科布博士）。此外，该项目汇集了两个跨越多个学科的计算生物学小组，以及其他经验丰富的儿科风湿病学研究人员。因此，该项目高度响应最新NIH路线图的目标。

DESCRIPTION (provided by applicant): We are entering an exciting era in pediatric rheumatology. New treatment approaches are improving the lives of children with juvenile idiopathic arthritis (JIA) to such a degree that it's now rare to see wheelchairs or crutches in our waiting rooms. Even splints, commonly used in the past to treat joint contractures, are seldom seen on our patients. Despite our progress, remission in JIA is rare. Recent work by our collaborator, Dr. Carol Wallace, has shown that only 5% of children with the polyarticular JIA (the most severe form of this disease) are in remission 5 years after diagnosis. Part of our problem in achieving remission is that, at the biological level, we don't really understand what "remission" is. It's a classic case of the difficulty of getting somewhere when you don't really know where you're trying to get. This grant application is about learning where we are trying to get. In this application, we aim to achieve a better understanding of what "remission" is using microarray-based biomarkers. Research from the Cobb (acute inflammation) and Jarvis (chronic inflammation) laboratories has demonstrated the feasibility of using genome-wide expression profiling can be used to define disease "states" (e.g., infected vs. not infected; in remission or not in remission). Furthermore, the Jarvis laboratory has demonstrated the promise of using these same technologies to predict clinical outcomes. For each group, these promising preliminary studies must be validated using larger patient populations and prospective study designs. In this application, we propose to validate peripheral blood biomarkers that already suggest that: (1) remission in juvenile arthritis can be identified at the molecular level through distinct gene expression signatures; (2) those signatures include the balance of both pro- and anti- inflammatory gene networks; and (3) the clinical course of children who reach an inactive disease state can be predicted based on molecular signatures that emerge in the peripheral blood mononuclear cells. Furthermore, we will take another step toward clinical application of this work by developing PCR-based whole blood assay to identify the most robust indicators of remission or clinical outcome. This project brings together two experienced investigators from two very different disciplines: pediatric rheumatology (Dr. Jarvis) and surgical intensive care (Dr. Cobb). Furthermore, the project brings together two computational biology groups spanning multiple disciplines, as well as other experienced pediatric rheumatology investigators. Thus, the project is highly responsive to the goals of the most recent NIH roadmap.