PATHOGENESIS OF A-R LYME ARTHRITIS THROUGH GEP/SYNOVIAL MARKERS IN JIA

通过 GEP/滑液标记物了解贾氏病中 A-R 莱姆关节炎的发病机制

• 批准号: 8360765
• 负责人: AnneMarie C Brescia
• 金额: $ 12.82万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360765
• 关键词: Adult; Biological Markers; Biology; Cell Line; Cells; Child; Childhood; Chondrocytes; Chondrogenesis; Chronic Childhood Arthritis; Coculture Techniques; Data; Disease; Fibroblasts; Funding; Future; Gene Expression; Gene Expression Profiling; Goals; Grant; Investigation; Joints; Lyme Arthritis; Molecular Profiling; National Center for Research Resources; Osteoblasts; Osteogenesis; Outcome; Pathogenesis; Pathology; Patients; Pediatric Research; Physicians; Positioning Attribute; Principal Investigator; Progressive Disease; Research; Research Infrastructure; Resources; Rheumatism; Rheumatoid Arthritis; Role; Sampling; Signal Pathway; Source; Synovial Fluid; Tissues; United States National Institutes of Health; Work; base; bone morphogenetic protein 4; cost; disability; joint destruction; member; outcome forecast; prevent; repository; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease of childhood. Although disease course is important in the outcome for patients, reliable predictors of disease course have not been identified. Additionally, the pathogenesis of this disease has yet to be elucidated. Our first hypothesis is that gene expression profiles of fibroblast-like synoviocytes (FLS) from the joints of children with JIA reflect intrinsic differences in synovial pathology early in disease which dictate disease course. We aim to identify synovial biomarkers capable of predicting disease course in JIA. Based on preliminary work, our second hypothesis is that dysregulation of the TGFb signaling pathway is central to the pathogenesis of JIA. Although significant work has been done on FLS from the joints of adult patients with rheumatoid arthritis (RA), investigations of these critical cells are lacking in children. We are in the unique position of having a rich repository of synovial fluid and tissue from which to obtain samples. We will use gene expression profiling of cultured FLS to identify differences in synovial biology in patients with differing disease courses. We will use these data to generate predictive synovial biomarkers to allow for determination of course early in disease. In addition, we will investigate the causal significance in the role of altered expression of members of the TGFb signaling pathway in the pathogenesis of JIA. Our preliminary studies revealed altered levels of members of the TGFb signaling pathways, including bone morphogenetic protein 4 (BMP4), in the FLS of patients with JIA when compared with controls. To further understand the relevance of these perturbations, we will examine the ability of FLS from JIA to promote chondrogenesis and osteogenesis using co-culture with cell lines known to differentiate along chondrocyte and osteoblast lineages upon stimulation with BMP4. Goals of this project are to identify predictive synovial biomarkers that can be used to anticipate course early in disease in JIA. This will allow physicians to provide accurate information regarding prognoses and help guide treatment decisions. Early prediction of children likely to develop progressive disease would allow earlier initiation of course-altering therapy to prevent joint destruction and disability. By defining the global transcriptional response of the synoviocyte in JIA, we will be much closer to understanding the underlying pathogenesis of this disease. Demonstrating the role of the TGFb signaling pathway in the pathogenesis of JIA has implications for future treatment options.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 幼年特发性关节炎（JIA）是儿童最常见的风湿性疾病。 虽然病程对患者的预后很重要，但尚未确定可靠的病程预测因子。 此外，这种疾病的发病机制尚未阐明。 我们的第一个假设是JIA儿童关节成纤维细胞样滑膜细胞（FLS）的基因表达谱反映了疾病早期滑膜病理学的内在差异，这决定了疾病的进程。 我们的目的是确定能够预测JIA病程的滑膜生物标志物。 基于初步工作，我们的第二个假设是TGF β信号通路的失调是JIA发病机制的核心。 虽然在成人类风湿性关节炎（RA）患者关节的FLS上已经做了大量的工作，但在儿童中缺乏对这些关键细胞的研究。 我们处于独特的地位，拥有丰富的滑液和组织库，可从中获取样本。 我们将使用培养FLS的基因表达谱来确定不同病程患者的滑膜生物学差异。 我们将使用这些数据来生成预测性滑膜生物标志物，以允许在疾病早期确定病程。 此外，我们将调查的因果关系的意义，在JIA的发病机制中的TGF β信号通路的成员的表达改变的作用。 我们的初步研究显示，与对照组相比，JIA患者的FLS中TGF β信号通路成员（包括骨形态发生蛋白4（BMP 4））的水平发生了变化。 为了进一步了解这些扰动的相关性，我们将使用与已知在BMP 4刺激后沿着软骨细胞和成骨细胞谱系分化的细胞系共培养来检查来自JIA的FLS促进软骨形成和成骨的能力。 该项目的目标是确定可用于预测JIA疾病早期病程的预测性滑膜生物标志物。 这将使医生能够提供有关乳腺癌的准确信息，并帮助指导治疗决策。 早期预测儿童可能发展为疾病进展将允许早期开始改变病程的治疗，以防止关节破坏和残疾。 通过定义关节炎滑膜细胞的整体转录反应，我们将更接近了解这种疾病的潜在发病机制。 证明TGF β信号通路在JIA发病机制中的作用对未来的治疗选择具有意义。