Characterization of the lupus nephritis microRNAome

摘要 本研究的目的是鉴定和表征微RNA(MiRNA)在血清外切体中的作用。 系统性红斑狼疮(SLE)的风险，以及SLE患者的风险和进展速度 至狼疮性肾炎(LN)。系统性红斑狼疮是一种典型的自身免疫性疾病，以抗核细胞的存在为特征。 自身抗体、补体激活和多系统器官损伤，包括LN，这是 发病率和死亡率很高，特别是在非洲裔美国人和美洲印第安人后裔中。这个 这种差距的基础仍然鲜为人知。尽管系统性红斑狼疮的病因尚不清楚，但基因组合 而环境因素起着因果作用。尽管发现了几个SLE易感基因座，但 仅DNA序列就只占常见复杂疾病的一小部分，并努力利用这些 用来对SLE临床病程进行分类或监测的标记物，以及LN的发展，还没有成功。近期 转录组测序的进展为将miRNAs表征为新的生物标志物提供了新的机会 可以显著改变SLE临床监测的范式。我们将检验最重要的假设 不同的血清外切体miRNAs将与SLE的存在相关，在SLE患者中， TO、LN和miRNAs通过改变靶基因影响LN严重程度和进展速度 表情。我们打算利用一个独特的机会，在一个大的祖先中探索这些关系 既有系统性红斑狼疮的多样化、特征良好的人群，又能利用 生物信息学和全转录组测序。我们的目标是描述外切体的影响 MiRNAs与SLE风险的关系以及在这些患者中，配对血液和靶点中LN的风险和节奏 组织填补了在SLE中发现、预防和管理LN所需知识的关键空白 以及确定新的治疗靶点。即将到来的调查结果将填补 关键差距与系统性红斑狼疮病因和进展的不同趋势有关，这些趋势因祖先而不同，并可能 转化为其他肾脏表型，包括在免疫介导的癌症中观察到的那些。

ABSTRACT The goal of this investigation is to identify and characterize the role of microRNAs (miRNA) in serum exosomes on the risk of Systemic Lupus Erythematosus (SLE), and among patients with SLE, the risk of, and rate of progression to, lupus nephritis (LN). SLE is a prototypic autoimmune disease that is characterized by the presence of antinuclear autoantibodies, complement activation and multisystem organ damage, including LN, which accounts for significant morbidity and mortality particularly among persons of African American and Amerindian ancestry. The basis for this disparity remains poorly understood. Although the etiology of SLE is unclear, combinations of genetic and environmental factors play a causal role. Despite the discovery of several SLE susceptibility loci, variation in DNA sequence alone accounts for only a small fraction of common complex disease and efforts to utilize these markers to classify or monitor SLE clinical course, and the development of LN, have not yet been successful. Recent advances in transcriptome sequencing offer new opportunities to characterize miRNAs as novel biomarkers, which could significantly change the paradigm of SLE clinical monitoring. We will test the overarching hypothesis that distinct serum exosome miRNAs will correlate with the presence of SLE and among patients with SLE, the presence of and time to, LN, and that miRNAs influence the severity and rate of progression of LN by altering target gene expression. We intend to capitalize on a unique opportunity to explore these relationships in a large, ancestry diverse, well-characterized population of established SLE while taking advantage of recent advances in bioinformatics and whole transcriptome sequencing. Our objective to characterize the influence of exosome miRNAs relative to the risk of SLE and among these patients, the risk and tempo of LN in paired blood and target tissue fills a critical gap in knowledge required to advance efforts to detect, prevent and manage LN among SLE patients, as well as to identify new therapeutic targets. Findings forthcoming from this investigation will fill a critical gap elated to the disparate trends of SLE etiology and progression, which differ by ancestry, and may translate to other kidney phenotypes including those observed in immune-mediated cancers.