UPITT Rheumatoid Arthritis Combined Center (UPITT RACC)

UPITT 类风湿性关节炎联合中心 (UPITT RACC)

• 批准号: 8851723
• 负责人: LARRY W MORELAND
• 金额: $ 25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851723
• 关键词: Antirheumatic Agents; Autoantibodies; Autoimmune Diseases; Automobile Driving; B-Lymphocytes; Bioinformatics; Biological; Biological Response Modifier Therapy; Biopsy; Biopsy Specimen; Blood; Blood Cells; CD4 Positive T Lymphocytes; Caring; Cell Count; Cells; Clinic Visits; Clinical; Clinical Data; Clinical Protocols; Clinical Research; Collaborations; Complex; Data; Data Quality; Disease; Enrollment; Epigenetic Process; Fibroblasts; Formalin; Funding; Heterogeneity; Immune; Immune response; In Vitro; Individual; Inflammatory; Institutional Review Boards; Joints; Lead; Lymphocyte; Measurement; Mediating; Medicine; Methods; Methotrexate; Operative Surgical Procedures; Orthopedic Procedures; Orthopedics; Outcome; Pathogenesis; Pathway interactions; Patients; Phase; Pilot Projects; Population; Population Heterogeneity; Positioning Attribute; Procedures; Process; Protocols documentation; RNA; Randomized; Recruitment Activity; Refractory; Registries; Replacement Arthroplasty; Research; Rheumatoid Arthritis; Sampling; Scientist; Services; Signal Pathway; Site; Source; Specialist; Specimen; Staging; Synovectomy; Synovitis; System; Systems Biology; T-Lymphocyte; TNF gene; Techniques; Therapeutic; Tissue Banking; Tissue Banks; Tissue Sample; Tissues; Ultrasonography; United States National Institutes of Health; Universities; Work; base; cohort; combinatorial; data management; data quality/integrity; experience; human tissue; improved; in vivo; inhibitor/antagonist; joint destruction; monocyte; public health relevance; response; rheumatologist; rituximab; tissue processing; transcriptome sequencing; validation studies

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a complex inflammatory disorder causing synovitis and joint destruction. Combinatorial use of disease-modifying anti-rheumatic drugs (DMARDs) as well as the advent of biologic agents has revolutionized therapeutic outcomes in RA. However, 40-50% of patients are refractory to any given therapy. The underlying immune mechanisms that define and predict clinical outcome remain unclear. In part, this is due to the paucity of data on pathways that are activated in the joint of patients at different stages of RA. The University of Pittsburgh has developed a strong collaborative team of clinicians and basic and translational scientists that is uniquely positioned to answer this nee through the Accelerated Medicines Partnership. Specifically, we offer a large cohort of RA patients under care of a single network of Pittsburgh rheumatologists; proven experience in recruiting patients for clinical registries and studies with accompanying sample banking: around one-quarter of our RA cohort are already enrolled in our active, NIH-funded research registry (RACER) through which clinical disease activity, labs, and blood are collected at each clinic visit; a state-of-the-art clinical data management and specimen tracking system; established collaborations to provide surgical samples (orthopaedics, IRB-approved), as well as ultrasound (US)-guided biopsies to be performed by specialists in this technique (IRB in process); expertise in tissue processing to isolate lymphocytes for advanced immune cell analytics; expertise in RNA-Seq, including analysis of human tissues (fresh and formalin-fixed) as well as bioinformatics; established workflow to perform all stages efficiently and rapidly at a single site to optimize data quality and integrity of these valuable samples. In UH2 Research Phase 0, we will establish standardized methods and feasibility parameters for tissue collection, processing, and analysis. Initially we will make use of readily-available synovial tissues from standard orthopaedic procedures such as joint replacement and synovectomy, and then validate these procedures on ultrasound-guided biopsy samples. In UH2 Research Phase I, we will then apply the standardized procedures developed in Phase 0 to determine heterogeneity between patient samples, compare RA versus OA and source of cells (blood vs. tissue, surgery vs. biopsy). These parameters will allow accurate power analysis to determine numbers of patients and types of analyses that are required for Phase II. In UH3 Research Phase II, we propose a controlled clinical study in which RA patients with active disease that have not responded to standard first-line therapy with methotrexate or TNF inhibitor will be randomized to receive biologic therapy. Joint biopsy and blood will be analyzed in relation to clinical outcome, and systems biology applied to determine causal pathway activation in relation to disease activity and therapy response. We also expect to participate in in-vitro and in-vivo validation studies based on pathways identified in Phase I, as well as emerging pilot project data.

 描述(申请人提供)：类风湿性关节炎(RA)是一种复杂的炎症性疾病，导致滑膜炎和关节破坏。疾病修饰性抗风湿药物(DMARDS)的联合使用以及生物制剂的出现使RA的治疗结果发生了革命性的变化。然而，40%-50%的患者对任何给定的治疗都是无效的。定义和预测临床结果的潜在免疫机制仍不清楚。这在一定程度上是由于缺乏有关患者关节中激活的通路的数据。 类风湿关节炎的不同阶段。匹兹堡大学已经建立了一支由临床医生、基础科学家和翻译科学家组成的强大的协作团队，该团队处于独特的地位，可以通过加速药物伙伴关系来满足这一需求。具体地说，我们提供一个由匹兹堡风湿科医生组成的单一网络照顾的大量RA患者队列；在招募患者进行临床登记和研究方面的成熟经验和附带样本库：我们大约四分之一的RA队列已经在我们活跃的、NIH资助的研究登记(RACER)中登记，通过该登记在每次临床访问时收集临床疾病活动、实验室和血液；最先进的临床数据管理和样本跟踪系统；建立合作提供手术样本(骨科，IRB批准)，以及由这项技术的专家在超声波(US)引导下进行活组织检查(IRB正在进行中)；在组织处理方面的专业知识，用于分离淋巴细胞以进行高级免疫细胞分析；在RNA-Seq方面的专业知识，包括对人体组织(新鲜的和福尔马林固定的)以及生物信息学的分析；建立了在单一地点高效和快速执行所有阶段的工作流程 以优化这些有价值的样本的数据质量和完整性。在UH2研究阶段0，我们将为组织收集、处理和分析建立标准化方法和可行性参数。首先，我们将利用标准骨科手术中容易获得的滑膜组织，如关节置换和滑膜切除术，然后在超声引导下的活检样本上验证这些手术。在UH2研究第一阶段，我们将应用在第0阶段开发的标准化程序来确定患者样本之间的异质性，比较RA与OA和细胞来源(血液与组织、手术与活检)。这些参数将允许准确的功率分析来确定第二阶段所需的患者数量和分析类型。在UH3研究第二阶段，我们提出了一项对照临床研究，在该研究中，对甲氨蝶呤或肿瘤坏死因子抑制剂的标准一线治疗没有反应的活动期RA患者将随机接受生物治疗。将分析关节活检和血液与临床结果的关系，并应用系统生物学来确定因果通路激活与疾病活动和治疗反应的关系。我们还希望参与基于第一阶段确定的途径的体外和体内验证研究，以及新出现的试点项目数据。