The Role of MicroRNA in Rheumatoid Arthritis Pathogenesis

MicroRNA 在类风湿关节炎发病机制中的作用

基本信息

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
项目类别：
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

项目摘要

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）：类风湿性关节炎（RA）的特征是慢性关节炎症以及软骨和骨质破坏。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，例如肿瘤坏死α (TNF-) 和白细胞介素β (IL-1ss)。抑制这些细胞因子可改善临床症状，并有效防止组织破坏的进展，有力地支持了这些细胞因子在 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。 MicroRNA (miRNA) 是最近发现的约 22 个核苷酸非编码形式的 RNA，对于多种生物学功能都很重要。它们表现出组织或发育阶段特异性表达模式，并开始与癌症或病毒感染等人类疾病相关。然而，目前关于 RA 中 miRNA 的表达或作用的信息有限。我们的初步研究结果表明，先天免疫反应的调节因子 miRNA-146 在 RA 滑膜组织中过度表达，并且在 TNF-α 和 TNF-α 刺激后，人类风湿性关节炎滑膜成纤维细胞 (RASF) 中 miRNA-146 的表达显着上调。 IL-1ss。此外，反义寡核糖核苷酸对 miRNA-146 的抑制揭示了对体外和体内炎症反应的治疗作用。基于这些观察，我们提出这样的假设：miRNA-146 是 RA 慢性免疫和炎症过程的调节因子，并且可能成为关节炎的新治疗靶点。我们提出以下具体目标：目标 1：详细描述 RA 滑膜组织中上调的 miRNA-146 和其他 miRNA 的表达模式；目标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。鉴定 RASF 中 miRNA-146 的新靶基因；目标 3：通过引入 miRNA-146 的反义寡核糖核苷酸，在患有胶原诱导性关节炎 (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 miRNA 的表征可能有助于我们了解 RA 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) 的特点是慢性滑膜炎以及随后的软骨和骨质破坏；然而，其病因和确切的发病机制仍不清楚。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 滑膜组织中表达上调。确定 miRNA-146 和其他 miRNA 在 RA 发病机制中的作用将增进我们对机制的理解，并为新的治疗策略打开大门。