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Joint-location specific pathogenic pathways in rheumatoid arthritis

类风湿性关节炎的关节部位特异性致病途径

基本信息

批准号：
10647624
负责人：
GARY S FIRESTEIN
金额：
$ 34.76万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10647624
关键词：
Affect Aggressive behavior Arthritis B-Lymphocytes Behavior Binding Binding Sites Biological Biological Assay Biology Cells Clinical Code Cytokine Signaling DNA Methylation Data Data Set Degenerative polyarthritis Development Diffuse Disease Distal Epigenetic Process Fibroblasts Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Hand Hip Joint Hip region structure Homeostasis IL6 Signaling Pathway Immune Individual Inflammation Inflammatory Arthritis Interleukin-6 Joints Knee Knee joint Lead Location Maps Mediating Medical Metacarpal bone Methods Methylation Molecular Profiling Pathogenesis Pathogenicity Pathway Analysis Pathway interactions Patients Pattern Phalanx Pharmaceutical Preparations Phenotype Play Production RNA Resolution Rheumatoid Arthritis Role Sample Size Signal Transduction Specificity Synovial Fluid Synovitis T cell response Testing Therapeutic Tissues Variant Wrist cell motility cytokine design differential expression genetic testing genome-wide imprint improved individual patient inhibitor joint destruction joint inflammation methylation pattern mouse model patient stratification response risk variant targeted treatment therapeutic development therapeutic target transcription factor transcriptome transcriptome sequencing transcriptomics treatment response

项目摘要

ABSTRACT Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we discovered differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signaling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-seq. This proposal is designed to dissect joint-specific epigenetic and functional aspects of RA. To accomplish this, we will 1) develop a high resolution map of joint-specific and disease- specific DNA methylation patterns in RA including pathway analysis that integrates genomics and transcriptomics data; 2) determine the functional consequences of differential epigenetic marks by evaluating joint-specific FLS transcriptome patterns and cytokine responses; and 3) determine the mechanisms that define joint specific epigenetic marks, with a focus on the role of transcription factor motifs. These joint-specific epigenetic and functional signatures suggest that RA disease mechanisms might vary from joint to joint and potentially explain some of the diversity of drug responses in RA patients.

摘要根据分子签名对患者进行分层可以促进靶向治疗的发展特定于特定疾病或组织位置的通路。以前的研究表明，糖尿病的发病机制类风湿性关节炎(RA)在所有受影响的关节中都是相似的。我们在这里展示了不同的DNA甲基化和转录组特征不仅区分RA成纤维细胞样滑膜细胞(FLS)和骨关节炎FLS，但也能区分分离于膝部和臀部的RA FLS。使用全基因组方法，我们发现 RA膝关节和髋关节FLS在编码生物通路的基因甲基化方面的差异，如 IL-6通过JAK-STAT途径进行信号传导。此外，膝关节之间的差异表达基因也被鉴定出来。和HIP FLS使用RNA-seq。这项建议旨在剖析关节特有的表观遗传学和功能性 RA的方方面面。为了实现这一点，我们将1)开发一张高分辨率的关节特定和疾病地图- RA中特定的DNA甲基化模式包括整合基因组学和转录组数据；2)通过评估确定差异表观遗传标记的功能后果关节特异的FLS转录组模式和细胞因子反应；以及3)决定定义联合的特定表观遗传标记，重点关注转录因子基序的作用。这些关节特定表观遗传学和功能特征表明，类风湿性关节炎的发病机制可能因关节而异这可能解释了类风湿关节炎患者药物反应的一些多样性。