Molecular and Cellular Dissection of Early Rheumatoid Arthritis

早期类风湿关节炎的分子和细胞解剖

• 批准号: 8851837
• 负责人: PETER K. GREGERSEN
• 金额: $ 25万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 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/8851837
• 关键词: Address; Affect; Biocompatible Materials; Biological; Biological Assay; Biology; Biopsy; Blood; Blood Cells; Blood specimen; Cartilage; Cell Line; Cell Separation; Cells; Cellular biology; Clinical; Cohort Studies; Collaborations; Complex; Cytometry; DNA; Data; Data Analyses; Data Set; Development; Diamond; Disease; Disease Progression; Dissection; Enrollment; Epigenetic Process; Etiology; European; Event; Feasibility Studies; Fibroblasts; Freezing; Generations; Genetic; Genetic Transcription; Health Care Costs; Heterogeneity; Immune; In Situ; Knowledge; Leadership; Leukocytes; Lupus Nephritis; Maps; Methods; Modification; Molecular; Molecular Analysis; Outcome; Pathogenesis; Pathology; Patients; Phase; Phenotype; Phosphorylation; Plasma; Population; Positioning Attribute; Preparation; Process; RNA; Recording of previous events; Research; Research Personnel; Resources; Rheumatoid Arthritis; Sample Size; Sampling; Signal Pathway; Sorting - Cell Movement; Staging; Synovial Cell; Synovial Membrane; System; Systemic Lupus Erythematosus; Techniques; Technology; Therapeutic; Tissues; Use of New Techniques; XCL1 gene; adaptive immunity; biobank; bone; cell type; clinical phenotype; cohort; design; effective therapy; genome-wide; illness length; molecular phenotype; new technology; novel therapeutics; peripheral blood; protein expression; public health relevance; response; single cell analysis; transcriptome sequencing; transcriptomics; validation studies

 DESCRIPTION (provided by applicant): While tremendous progress has been made in genetic definition and biological treatments for rheumatoid arthritis (RA), there remains a lack of fundamental knowledge about the pathogenesis and heterogeneity of this disorder. Recent technological developments allow for precise molecular analysis of disease tissues down to the single cell level. We propose to interrogate circulating immune cells and synovial tissue cells to identify the molecular and cellular correlates between systemic immune cell diversity, synovial pathology and clinical phenotypes. In Specific aim 1 (phase 0), we will optimize processes for the preparation and storage of synovial tissue and peripheral blood leukocyte samples in order to support a variety of advanced analytic techniques. These include single cell RNA seq of synovial tissue cells, epigenetic studies (ATAC-Seq), CyTOF mass cytometry for high-dimensional analysis of cellular phenotypes, and RNA seq analysis of at least 12 peripheral blood leukoctye subsets. We will also support development and feasibility studies of novel technologies for in situ molecular and cellular analysis of histological sections of synovial tissu. In addition, we will develop synovial cell lines to enable detailed study of synovial cell biology.In Specific Aim 2 (phase 1), we will enroll 30 subjects with rheumatoid arthritis for study of blood and synovial tissue using the technologies developed and validated in phase 0. A systems level analysis of these data will drive the selection of specific assays to be utilized in a larger patiet cohort. In Specific Aim 3 (phase 2), we will carry out an observational cohort study of 250 early RA patients enrolled over a three year period with analysis of both synovial tissue and peripheral blood leukocytes. We will employ a set of focused assays that emerge from the studies in Phase 0 and 1. The disease course, therapy and response to therapy will be documented in all patients. We will address the following hypotheses: 1) multiparameter analysis of synovial tissue can define subsets of disease with distinct clinical features or outcomes; 2) analysis of peripheral blood cell subsets with high dimensional molecular and cellular data, can identify correlates for these disease subsets; 3) useful parameters can be developed that can identify, as well as predict, therapeutic response.

 描述（由适用提供）：虽然在类风湿关节炎（RA）的遗传定义和生物治疗中取得了巨大进展，但仍缺乏 关于这种疾病的发病机理和异质性的基本知识。最近的技术发展允许对疾病时间到单细胞水平的疾病时间进行精确的分子分析。我们建议询问循环的免疫细胞和滑膜细胞，以鉴定全身免疫力多样性，滑膜病理学和临床表型之间的分子和细胞相关。在特定的目标1（阶段0）中，我们将优化用于制备和存储滑膜组织和外周血白血病样品的过程，以支持各种高级分析技术。这些包括滑膜细胞的单细胞RNA SEQ，表观遗传学研究（ATAC-SEQ），用于细胞表型的高维分析的质量细胞仪以及至少12个外周血血液白细胞分子的RNA SEQ分析。我们还将支持对滑膜组织组织学切片的原位分子和细胞分析的新技术的发展和可行性研究。此外，我们将开发滑膜细胞系以详细研究滑膜细胞生物学。在特定的目标2（阶段1）中，我们将使用在0阶段0中开发并验证的技术来招募30名患有类风湿关节炎的受试者，以研究血液和滑膜组织。这些系统水平分析将推动这些数据级别的选择，以驱动这些特定的分析来选择大型Patiet cohort。在特定的目标3（第2阶段）中，我们将对在三年内入学的250名早期RA患者进行观察队列研究，并分析滑膜组织和外周血白细胞。我们将采用一系列重点评估，这些评估从第0期和第1阶段的研究中出现。所有患者的疾病病程，治疗和对治疗的反应都将记录下来。我们将解决以下内容。假设：1）滑膜组织的多参数分析可以定义具有不同临床特征或结局的疾病子集； 2）分析具有高维分子和细胞数据的外周血细胞亚群可以鉴定这些疾病子集的相关性； 3）可以开发有用的参数，并可以识别并预测治疗反应。