The Role of MicroRNA in Rheumatoid Arthritis Pathogenesis

MicroRNA 在类风湿关节炎发病机制中的作用

• 批准号: 7793402
• 负责人: HIROSHI ASAHARA
• 金额: $ 29.61万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7793402
• 关键词: Address; Adverse event; Antibodies; Antisense Oligonucleotides; Apoptosis; Area; Arthritis; B-Lymphocytes; Biological Process; Cartilage; Cell Line; Cell Proliferation; Cells; Chronic; Clinical; Collagen; Collagen Arthritis; Data; Degenerative polyarthritis; Development; Drug usage; Etiology; Exhibits; Fibroblasts; Functional RNA; Future; Gene Expression; Gene Targeting; Genes; Heart failure; Human; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innovative Therapy; Interleukins; Knee joint; Lymphoma; Malignant Neoplasms; Mediating; MicroRNAs; Mus; Necrosis; Nucleotides; Oligoribonucleotides; Pathogenesis; Patients; Pattern; Process; Production; Proliferating; Publications; RNA; Reporting; Research; Rheumatoid Arthritis; Risk; Role; Small RNA; Staging; Stromelysin 1; Symptoms; Synovial Cell; Synovitis; T-Lymphocyte; TNF gene; TNF receptor-associated factor 6; Testing; Therapeutic Effect; Tissues; Tumor Necrosis Factor-alpha; Virus Diseases; base; bone; calin; cytokine; human TNF protein; human disease; improved; in vivo; inhibitor/antagonist; interleukin-1 receptor-associated kinase; macrophage; new therapeutic target; novel; novel therapeutics; overexpression; prevent; promoter; public health relevance; response; tumor

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and cartilage and bone destruction. The synovial lining cells proliferate and the tissue is infiltrated by macrophages, T cells, and B lymphocytes. These cells are activated and produce inflammatory cytokines, such as tumor necrosis alpha (TNF-) and interleukin beta (IL-1ss). Inhibition of these cytokines improves the clinical symptoms and is effective in preventing progression of tissue destruction, strongly supporting the importance of these cytokines in RA. Despite this important progress, the etiology of RA remains unclear. MicroRNAs (miRNAs) are recently discovered ~22 nucleotide non-coding forms of RNA and are important for a diverse range of biological functions. They exhibit tissue or developmental stage specific expression patterns and are beginning to be associated with human diseases such as cancer or viral infection. However, currently there is limited information on the expression or role of miRNAs in RA. Our preliminary findings show that miRNA-146, a regulator of innate immune responses, is overexpressed in RA synovial tissues, and the expression of miRNA-146 is markedly up-regulated in human rheumatoid arthritis synovial fibroblast (RASF) after stimulation with TNF- and IL-1ss. Furthermore, inhibition of miRNA-146 by antisense oligoribonucleotides revealed therapeutic effects on inflammatory responses both in vitro and in vivo. Based on these observations, we propose the hypothesis that miRNA-146 is a regulator of the chronic immune and inflammatory process in RA and could be a novel therapeutic target for arthritis. We propose the following specific aims: Aim 1: Characterize in detail the expression patterns of miRNA-146 and of other miRNAs that are upregulated in RA synovial tissues; Aim 2: Examine the function of miRNA-146 in regulating synovial cell proliferation, anti-apoptosis and production of inflammatory mediators. Identify novel target genes of miRNA-146 in RASF; and Aim 3: Examine the role of miRNA-146 in inflammatory arthritis in vivo in mice with collagen-induced arthritis (CIA) by introduction of antisense oligoribonucleotides for miRNA-146. Characterization of RA specific miRNAs may help us to understand RA pathogenesis and provide novel therapeutic targets. PUBLIC HEALTH RELEVANCE. Rheumatoid arthritis (RA) is characterized by chronic synovitis and subsequent cartilage and bone destruction; however, its etiology and precise pathogenetic mechanisms remain unclear. Here, we will characterize miRNA-146, which belongs to the recently identified non-coding small RNAs and is upregulated in RA synovial tissue. Determining the role of miRNA-146 and other miRNAs in RA pathogenesis will advance our understanding of mechanisms and open the door for novel therapeutic strategies.

描述（由申请人提供）：风湿性关节炎（RA）的特征是慢性关节炎症以及软骨和骨破坏。滑膜衬里细胞增殖，组织被巨噬细胞、T细胞和B淋巴细胞浸润。这些细胞被激活并产生炎性细胞因子，如肿瘤坏死因子α（TNF-α）和白细胞介素β（IL-1 β）。这些细胞因子的抑制改善了临床症状，并有效地防止组织破坏的进展，强烈支持这些细胞因子在RA中的重要性。尽管取得了这一重要进展，但RA的病因仍不清楚。微小RNA（microRNAs，miRNAs）是近年来发现的一种约22个核苷酸的非编码RNA，具有重要的生物学功能。它们表现出组织或发育阶段特异性表达模式，并开始与人类疾病如癌症或病毒感染相关。然而，目前关于miRNA在RA中的表达或作用的信息有限。我们的初步研究结果表明，miRNA-146，先天免疫反应的调节剂，在RA滑膜组织中过表达，并在人类风湿关节炎滑膜成纤维细胞（RASF）与TNF-α和IL-1 β刺激后，miRNA-146的表达显着上调。此外，通过反义寡核苷酸抑制miRNA-146揭示了对体外和体内炎症反应的治疗作用。基于这些观察结果，我们提出了一个假设，即miRNA-146是RA慢性免疫和炎症过程的调节因子，可能是关节炎的一个新的治疗靶点。我们提出以下具体目标：目的1：详细描述miRNA-146和其他在RA滑膜组织中上调的miRNA的表达模式;目的2：检查miRNA-146在调节滑膜细胞增殖、抗凋亡和炎症介质产生中的功能。目的3：通过引入miRNA-146的反义寡核苷酸，在患有胶原诱导的关节炎（CIA）的小鼠体内检查miRNA-146在炎症性关节炎中的作用。RA特异性miRNAs的鉴定有助于我们了解RA的发病机制，并提供新的治疗靶点。 公共卫生相关性。类风湿性关节炎（RA）是一种以慢性滑膜炎及软骨和骨破坏为特征的疾病，其病因和确切的发病机制尚不清楚。在这里，我们将表征miRNA-146，它属于最近发现的非编码小RNA，在RA滑膜组织中上调。确定miRNA-146和其他miRNA在RA发病机制中的作用将促进我们对机制的理解，并为新的治疗策略打开大门。