Evolving Adaptive and Effector Mechanisms from Pre-RA through Established Disease

从 RA 前期到已确定疾病的适应性和效应机制的演变

• 批准号: 9323969
• 负责人: Vernon Michael Holers
• 金额: $ 9.2万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323969
• 关键词: Antigens; Arthritis; Autoantibodies; Autoantigens; B-Lymphocytes; Biopsy; Cartilage; Cell Lineage; Cells; Chronic; Clinical; Clinical Investigator; Clinical Research; Clinical assessments; Collaborations; Data Set; Development; Disease; Disease remission; Educational Curriculum; Effectiveness; Effector Cell; Environmental Exposure; Epigenetic Process; Etiology; Evaluation; Evolution; Exhibits; Fibroblasts; Genotype; Goals; Health; Heterogeneity; Immune system; Inflammation; Link; Lymphocyte; Medicine; Methods; Molecular; Natural History; Onset of illness; Osteoclasts; Pathway interactions; Patients; Performance; Phase; Pilot Projects; Population; Prevention; Procedures; Process; Recording of previous events; Research; Research Infrastructure; Research Personnel; Rheumatoid Arthritis; Sampling; Sampling Studies; Signal Transduction; Signs and Symptoms; Site; Staging; Subgroup; Synovial Membrane; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Teaching Method; Techniques; Technology; Testing; Therapeutic Intervention; Tissue Sample; Tissues; Training; Ultrasonography; Universities; arm; base; bone loss; cohort; design; education evaluation; high risk; imprint; improved; innovative technologies; inter-institutional; monocyte; new technology; novel; peripheral blood; professor; programs; response; single cell technology; therapeutic target; tool; transcriptome sequencing

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a disease that sequentially progresses through several stages from its earliest asymptomatic origins characterized by autoantibodies alone through to a fully established and chronic destructive arthritis. Established RA is also characterized by several phenotypic subgroups that vary by genotype, autoantibodies, and environmental exposures. The central hypothesis of this Clinical and Technology Research Site (CTRS) proposal is that RA can be deconstructed such that novel disease stage- and cell lineage-specific therapeutic targets can be identified through the comprehensive evaluation of the linked adaptive and effector arms of the immune system. Reflecting this focus over the full spectrum of disease, the study is designated EMORA (Evolving Mechanisms of Rheumatoid Arthritis). In aggregate, the EMORA clinical and technology site investigators have several existing cohorts and decades of successful collaborations, and together constitute an integrated network of sites with clinical studies expertise, advanced technologies to identify and characterize antigen-specific lymphocytes, and capabilities to process and study synovium using many innovative technologies. EMORA will utilize a core strategy wherein paired peripheral blood and synovial samples are obtained and studied in a highly coordinated manner, and populations of T and B lymphocytes, fibroblast like synoviocytes and monocytic osteoclast precursors will be evaluated as single cells and small homogeneous populations. Using these approaches, EMORA investigators will test three primary hypotheses: 1) Novel mechanisms of disease and distinct therapeutic targets in RA can be discovered that will vary by the stage of development of disease, ranging from subjects at extraordinarily high risk for incipient clinical disease onset through to those with established RA under treatment, 2) Therapeutic targets will be identifiable in both antigen-specific circulating and tissue infiltrating B and T cells that react with RA- related autoantigens, necessitating paire studies of both peripheral blood and synovium, and 3) Exploration of networks of synovial "effector" cells including fibroblast-like synoviocytes and monocytic osteoclast precursors, identified in both peripheral blood and synovium, will identify novel pathways and related disease targets that drive inflammation, cartilage destruction and bone loss. Finally, to develop expertise going forward in ultrasound-guided synovial biopsy techniques, a `hands-on" procedural education and evaluation program for USA investigators has been developed with Professor Paul Emery at the University of Leeds.

 描述（由应用提供）：类风湿关节炎（RA）是一种疾病，从最早的不对称起源从单独进行自身抗体到完全建立和慢性破坏性关节炎的疾病依次进行多个阶段。建立的RA还以基因型，自身抗体和环境暴露变化的几个表型亚组的特征。该临床和技术研究地点（CTRS）建议的核心假设是可以解构RA，以使新的疾病阶段和细胞谱系特异性的治疗靶标可以通过对免疫系统的链接适应性和效应子的全面评估来确定。该研究反映了这一重点是疾病的全部疾病，被指定为Emora（类风湿关节炎的发展机制）。总体而言，emora临床和技术现场研究人员拥有几个现有的队列和数十年的成功合作，并且共同构成了与临床研究专业知识，高级技术的集成网站网络，可识别和表征抗原特异性淋巴细胞，以及使用许多创新技术来处理和研究合成的能力。 Emora将利用一种核心策略，以高度协调的方式获得并研究了成对的外围血液和滑膜样品，并且T和B淋巴细胞的种群，像滑膜细胞（类似于单核细胞的成纤维细胞）以及单核细胞前体的前体将被评估为单个细胞和小均值同型群体。使用这些方法，Emora研究人员将检验三个主要假设：1）可以发现RA中疾病的新型机制和不同的治疗靶标，可以随着疾病的发展阶段而有所不同，范围从具有高度高的初期临床疾病的高风险到具有RA的既定RA的受试者的范围不等。 Under treatment, 2) Therapeutic targets will be identified in both antigen-specific circulating and tissue infiltrating B and T cells that react with RA-related autoantigens, necessary padire studies of both peripheral blood and synovium, and 3) Exploration of networks of synovial "effector" cells including fibroblast-like synoviocytes and monocytic osteoclast precursors, identified in both外周血和滑膜，将确定驱动感染，软骨破坏和骨质流失的新型途径和相关疾病靶标。最后，为了开发超声引导的滑膜活检技术的专业知识，已经与利兹大学的保罗·埃默里（Paul Emery）一起开发了美国研究人员的“动手”程序教育和评估计划。