特发性皮肌炎外周血及肺脏microRNA表达谱及功能研究

项目名称： 特发性皮肌炎外周血及肺脏microRNA表达谱及功能研究

项目编号： No.81471615

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王迁

作者单位： 中国医学科学院北京协和医院

项目金额： 60万元

中文摘要： 特发性皮肌炎（DM）是一种累及皮肤、肌肉的炎症性自身免疫病，东亚患者易合并肺间质病变（ILD），其机制不清，常迅速进展为呼吸衰竭，死亡率极高，亟需提高诊断水平并探索新的治疗靶点。小分子RNA（miRNAs）调控异常可引起多种自身免疫病，其表达谱和功能研究已成为揭示细胞内分子调控机制的有力工具。本课题在已建立系统性红斑狼疮和系统性硬化症miRNAs表达谱的研究平台基础上，高通量筛选DM外周血单个核细胞和血浆中异常的miRNAs表达谱；通过大样本临床与标本库进一步筛选与肺部病变相关的调控炎症和促纤维化因子表达的miRNAs，并在DM-ILD患者肺组织中进行验证；利用小鼠肺上皮细胞和进行miRNAs对靶基因的功能研究和验证；采用对DM-ILD较特异的抗MDA5抗体处理肺上皮细胞，探索其在miRNA水平的促炎和致纤维化机制，试图在miRNAs水平将自身免疫、上皮细胞损伤和纤维化三方面机制联系起来，

中文关键词： 皮肌炎；自身免疫疾病；肺间质病变；发病机制；微小RNA

英文摘要： Idiopathic dermatomyositis (DM) is an inflammatory autoimmune disease which mainly involving skin and skeletal muscle. East asian DM patients are at high risk of developping interstitial lung diseae (ILD) with unknown etiology, which often rapidly progresses to respiratory failure and the mortality is extremely high. Novel diagnostic tools and therapeutic targets are critically required. MicroRNAs (miRNAs) dysregulation can result in many autuimmune diseases, and its expression profiling and functional study have become useful tools in demonstrating intracellularly molecular regulation. This study aims to perform a high-flux screening of aberrant miRNAs profile in peripheral blood mononuclear cells and lung tissue on a pre-established miRNA study platform, which had successfully validated in the similar study of systemic lupus erythematosus and systemic sclerosis. The study will screen further on the miRNAs which regulating ILD-related inflammation and the expression of profibrotic cytokines through a large-sample clinical registry and biobank. The selected miRNAs will be validated in lung tissue of DM-ILD patients. The function of selected miRNAs on target genes will be studied and validated in mice lung epithelia. In addition, the lung epithilia will be processed by DM-ILD specific anti-MDA5 antibody and the change of selected miRNAs' expression will be detected, which will demonstrate the pathogenesis of DM-ILD by combining autoimmunity, epithelial injury and fibrosis.

英文关键词： dermatomyositis;autoimmune disease;interstitial lung dissease;pathogenesis;microRNA