Microarray-Based Biomarkers in Juvenile Idiopathic Arthritis

描述(由申请人提供)： 我们正在进入儿科风湿病的一个激动人心的时代。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，以至于现在我们的候诊室里很少看到轮椅或拐杖。即使是过去常用来治疗关节痉挛的夹板，在我们的患者身上也很少见。尽管我们取得了进展，但JIA的缓解情况很少见。我们的合作者Carol Wallace博士最近的研究表明，患有多关节JIA(这种疾病最严重的形式)的儿童中，只有5%在诊断后5年内得到缓解。我们在实现缓解方面的部分问题是，在生物学层面上，我们并不真正理解什么是“缓解”。这是一个经典的例子，当你不知道自己要去哪里的时候，你很难到达某个地方。这项拨款申请是为了了解我们想要达到的目标。在这项申请中，我们的目标是更好地理解使用基于微阵列的生物标记物的“缓解”是什么。Cobb(急性炎症)和Jarvis(慢性炎症)实验室的研究表明，使用全基因组表达谱可用于定义疾病“状态”(例如，感染与未感染；缓解或不缓解)的可行性。此外，Jarvis实验室已经展示了使用这些相同的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群体和前瞻性研究设计来验证。在这一应用中，我们建议验证外周血液生物标记物，这些标记物已经表明：(1)可以通过不同的基因表达签名在分子水平上识别青少年关节炎的缓解；(2)这些签名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签名来预测达到非活动期疾病状态的儿童的临床病程。此外，我们将通过开发基于PCR的全血检测来确定最可靠的缓解或临床结果指标，从而朝着这项工作的临床应用又迈进一步。这个项目汇集了来自两个非常不同学科的两名经验丰富的研究人员：儿科风湿病(贾维斯医生)和外科重症监护(科布医生)。此外，该项目汇集了跨越多个学科的两个计算生物学小组，以及其他经验丰富的儿科风湿病研究人员。因此，该项目高度响应了美国国立卫生研究院最新路线图的目标。 公共卫生相关性： 该项目旨在开发生物标记物，使我们能够知道幼年特发性关节炎儿童何时达到缓解状态。我们还将开发标记物，使我们能够预测看起来情况良好的儿童的病程。拥有这些标志物将是开发更好的方法来管理患有这种常见慢性病的儿童的重要组成部分。

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. PUBLIC HEALTH RELEVANCE: This project is aimed at developing biological markers that will allow us to know when children with juvenile idiopathic arthritis have reached remission. We will also develop markers that will allow us to predict the disease course in children who appear to be doing well. Having these markers will be an important part of developing better ways to manage children with this common chronic disease.