Transcriptomics in synoviocytes defines pathogenesis of rheumatoid arthritis

滑膜细胞的转录组学定义了类风湿性关节炎的发病机制

基本信息

批准号：
9337242
负责人：
Kamil Slowikowski
金额：
$ 3.16万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9337242
关键词：
Affect Architecture Autoimmune Process B-Lymphocytes Biological Biological Assay Biology Cartilage Cell Line Cell Separation Cell physiology Cells Cellular Structures Characteristics Chronic Chronic Kidney Failure Connective Tissue Data Dimensions Disease Disease Progression Dose Encapsulated Etiology Experimental Designs Feedback Fibroblasts Fibrosis Fluorescence-Activated Cell Sorting Fresh Tissue Gene Expression Genes Genetic Transcription Hyperplasia Immune Immune system Individual Inflammation Inflammatory Interleukin-17 Interleukins Interstitial Pneumonia Joint Capsule Joints Knowledge Lead Liver Cirrhosis Mediating Membrane Methods Molecular Molecular Profiling Morphologic artifacts Operative Surgical Procedures Osteoclasts Pathogenesis Pathogenicity Pathway interactions Patients Pilot Projects Population Psoriasis Recruitment Activity Replacement Arthroplasty Rheumatoid Arthritis Sampling Signal Transduction Signaling Molecule Statistical Data Interpretation Statistical Methods Structure Synovial Fluid Synovial Membrane T-Lymphocyte TNF gene Thinness Time Tissues Variant Work activating transcription factor angiogenesis articular cartilage bone bone erosion cell motility cell type cytokine dosage experimental study improved innovation insight joint destruction knock-down new therapeutic target novel novel marker response single cell sequencing transcriptomics

项目摘要

Project Summary Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects millions of people worldwide. Disease progression includes inflammation of the synovium, a membrane that encapsulates the joint and contains the synovial fluid. The synovium, composed mostly of fibroblasts, is central to disease pathogenesis in RA. It forms an invasive tissue called pannus that recruits immune cells such as T cells and B cells, destroys articular cartilage in the joint, and mediates signaling leading to activation of bone-resorbing osteoclasts. In this project, we will study synovial fibroblasts obtained from fresh tissue discarded during joint replacement surgery. Our work will define the cellular population structure of fibroblasts in the synovium by assaying single-cell gene expression profiles. In RA, the synovium has a heterogeneous mixture of signaling molecules and cell types that influence a positive feedback loop between the tissue and the cells of the immune system. This project aims to define a detailed transcriptional network synergistically activated by tumor necrosis factor (TNF) and interleukin 17 (IL17A). This work will establish basic knowledge about the transcriptional functions of synovial fibroblasts, so it may have broad implications for RA and other diseases that are mediated by fibroblasts in connective tissues such as psoriasis and interstitial pneumonia.

项目概要类风湿性关节炎 (RA) 是一种影响全球数百万人的慢性炎症性疾病。疾病进展包括滑膜炎症，滑膜是一种包裹关节并含有滑液。滑膜主要由成纤维细胞组成，是 RA 疾病发病机制的核心。它形成一种称为血管翳的侵入性组织，它会招募 T 细胞和 B 细胞等免疫细胞，破坏关节关节软骨，并介导导致骨吸收破骨细胞激活的信号传导。在这个项目中，我们将研究从关节置换手术期间丢弃的新鲜组织中获得的滑膜成纤维细胞。我们的这项工作将通过分析单细胞基因来确定滑膜中成纤维细胞的细胞群结构表达谱。在 RA 中，滑膜具有信号分子和细胞类型的异质混合物影响免疫系统组织和细胞之间的正反馈循环。本项目旨在定义由肿瘤坏死因子（TNF）协同激活的详细转录网络白细胞介素 17 (IL17A)。这项工作将建立有关滑膜转录功能的基础知识成纤维细胞，因此它可能对 RA 和其他由成纤维细胞介导的疾病具有广泛的影响结缔组织，如牛皮癣和间质性肺炎。