Gene Expression in Pediatric Arthritis

描述(由申请者提供)：本计划项目续期寻求在第一个周期的成功基础上再接再厉，在第一个周期中，关于青少年特发性关节炎(JIA)儿童外周血中的基因表达取得了许多令人兴奋的发现。这一建议利用了在第一个周期中进行的大量投资，这些投资为进一步的研究提供了宝贵的资源，包括大型基因表达数据集、大量生物样本(DNA、RNA、全血RNA、外周血单个核细胞(PBMC)RNA、血浆和血清)以及完善的样本收集和分析基础设施。第一个周期最重要的发现之一是确定了基因表达“特征”，这些特征表明了几个JIA亚型之间和内部的异质性。这些标记不仅有助于通过提供分子表型来重新定义JIA类别，而且还可能提供对JIA基本病理生物学过程的洞察，潜在地暗示对治疗的不同反应，以及理解JIA遗传易感性的新联系。例如，在许多老年多关节JIA患者中表达的“T细胞特征”似乎预示着对甲氨蝶呤的反应不足，它也与JIA可能的易感基因的表达增加有关。本次更新中提出的四个项目协同处理了第一个周期中的调查结果提出的关于联合免疫分析中基因表达的重要问题；利用了第一个周期中开发的数据、样本和基础设施。在项目1中，Griffin博士将研究与多关节和少关节JIA中识别的三个基因表达特征相关的细胞病理生物学。在项目2中，洛维尔博士将研究这些特征与临床对甲氨蝶呤和抗肿瘤坏死因子生物学反应的关系，并确定PBMC基因表达谱是否有助于指导药物缓解期患者停用抗肿瘤坏死因子药物。在项目3中，汤普森博士将研究与JIA基因表达差异有显著联系的遗传易感基因。在项目4中，格罗姆博士将使用基因表达谱来研究系统性JIA患者的单核细胞样细胞的病理生物学。所有四个项目都将得到行政(格拉斯博士)、组织(汤普森博士)和信息学(瓦格纳博士)核心的支持，这将促进资源的有效利用。基因表达谱为提高JIA的病理生物学、临床结果和遗传相关性的知识提供了一种分子方法，该计划项目中的发现有可能显著改善JIA的诊断和管理。

DESCRIPTION (provided by applicant): This Program Project renewal seeks to build upon the success of the first cycle, where many exciting discoveries were made regarding gene expression in peripheral blood of children with Juvenile Idiopathic Arthritis (JIA). This proposal takes advantage of significant investments made in the first cycle that produced valuable resources for further studies, including a large gene expression dataset, a substantial collection of biological samples (DNA, RNA, whole blood for RNA, peripheral blood mononuclear cells (PBMC) for RNA, plasma, and serum), and a well-developed infrastructure for sample collection and analysis. Among the most important findings of the first cycle was identification of gene expression "signatures" that indicated heterogeneity among and within several JIA subtypes. These signatures may not only contribute to redefining JIA categories by offering molecular phenotypes, but also may provide insight into fundamental pathobiological processes in JIA, with potential implications for differential responses to treatments, and novel links to understanding genetic susceptibility to JIA. For example, a "T Cell Signature" expressed in many older polyarticular JIA patients appears to predict inadequate responses to methotrexate, and it is also associated with increased expression of putative JIA susceptibility loci. The four projects proposed in this renewal synergistically approach important questions regarding gene expression in JIA that have been raised by findings in the first cycle; leveraging data, samples and infrastructure developed in the first cycle. In Project 1, Dr. Griffin will investigate cellular pathobiology associated with three gene expression signatures identified in polyarticular and oligoarticular JIA. In Project 2, Dr. Lovell will investigate the relationship of these signatures with clinical responses to methotrexate and anti-TNF biologies, as well as determine if PBMC gene expression profiling can help guide withdrawal of anti-TNF agents from patients in remission on medication. In Project 3, Dr. Thompson will investigate genetic susceptibility loci that have remarkable connections to gene expression differences in JIA. In Project 4, Dr. Grom will use gene expression profiling to study pathobiology of monomyelocytoid cells in systemic-onset JIA. All four projects will be supported by Administrative (Dr. Glass), Tissue (Dr. Thompson), and Informatics (Dr. Wagner) Cores that will facilitate efficient and effective use of resources. Gene expression profiling offers a molecular approach for advancing knowledge of pathobiology, clinical outcomes and genetic associations in JIA, with discoveries made in this Program Project having the potential to dramatically improve diagnosis and management of JIA.