Identification of key regulators in rheumatoid arthritis

类风湿关节炎关键调节因子的鉴定

• 批准号: 9976210
• 负责人: GARY S FIRESTEIN
• 金额: $ 60.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9976210
• 关键词: ATAC-seq; Affect; Aggressive behavior; Binding; Biological; Biological Assay; Biological Process; Biopsy; Cartilage; Cell Lineage; Chromatin; Critical Pathways; DNA; DNA Methylation; Data; Data Set; Degenerative polyarthritis; Development; Diffuse; Disease; Effector Cell; Enhancers; Environmental Risk Factor; Enzymes; Epigenetic Process; Fibroblasts; Genes; Genetic; Genetic Variation; Hand; Hip Joint; Human Genome; Immune; Individual; Interleukin-6; Italy; Joints; Knee; Knee joint; Maps; Measurement; Measures; Mediating; Mediator of activation protein; Medical; Methods; Modification; Molecular; Names; Natural Immunity; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Play; Production; Regulation; Replacement Arthroplasty; Rheumatoid Arthritis; Role; Sampling; Signal Pathway; Surveys; Synovial Membrane; Synovitis; Tai Ji; Text; Therapeutic Agents; Variant; Work; Wrist; computational pipelines; cost; differential expression; effective therapy; epigenomics; experimental study; genetic variant; genome sequencing; genome-wide; histone modification; improved; individual patient; insight; joint injury; methylome; personalized medicine; promoter; response; transcription factor; transcriptome; transcriptome sequencing; treatment response; whole genome

Project Summary Joint damage and synovial inflammation in rheumatoid arthritis (RA) are influenced by genetic and environmental factors. Individual patients and joints have shown variation of response to the same treatment. To reveal the underlying mechanisms, genome-wide characterization of the RA pathogenesis that require small amount of input materials and at relatively low cost is necessary. Currently, RNA-seq and ATAC-seq satisfy these requirements to map transcriptome and open chromatin in the RA samples, which can provide complementary delineation of the pathogenic mechanisms. We propose here to perform RNA-seq and ATAC- seq in fibroblast-like synoviocytes (FLS) for both RA and osteoarthritis (OA) patients. We will develop and improve a new computational pipeline that integrates these data to evaluate each transcription factor's importance in individual patients. By comparing FLS RA and OA samples, we will identify disease-specific regulators in Specific Aim 1. By comparing individual RA patients, we will identify patient-specific regulators in Specific Aim 2. We will perform biologic experiments to validate the top predicted regulators in Specific Aim 3. Once completed, this study will open a new avenue of understanding the regulatory mechanisms underlying RA and dictating the variable responses to treatment in individual patients, which paves the way towards precise and personalized therapy.

项目摘要 类风湿性关节炎（RA）的关节损伤和滑膜炎症受遗传和 环境因素个体患者和关节对相同治疗的反应存在差异。 为了揭示潜在的机制，RA发病机制的全基因组特征需要 需要少量输入材料和相对较低的成本。目前，RNA-seq和ATAC-seq 满足这些要求，以映射RA样品中的转录组和开放染色质，这可以提供 对致病机制的补充描述。我们建议在这里进行RNA-seq和ATAC- 在RA和骨关节炎（OA）患者的成纤维细胞样滑膜细胞（FLS）中的seq。创新和 改进一个新的计算管道，整合这些数据，以评估每个转录因子的 对个别患者的重要性。通过比较FLS RA和OA样本，我们将确定疾病特异性 具体目标1中的监管机构。通过比较单个RA患者，我们将确定患者特异性调节剂， 具体目标2。我们将进行生物实验，以验证特定目标3中预测的最佳调节器。 一旦完成，这项研究将打开一个新的途径，了解监管机制的基础 RA并决定个体患者对治疗的可变反应，这为 精准的个性化治疗