MicroRNA expression in the NZB/W lupus mouse

描述(申请人提供)：对系统性红斑狼疮(SLE)的遗传和环境病原体的广泛分析尚未揭示疾病发生的共同机制。最近发现的microRNAs(MiRNAs)引发了一系列关于miRNAs如何调控基因表达的研究。大量证据表明，miRNA系统有助于调节多种正常的细胞功能和病理。我们最近已经证明了miRNAs在免疫细胞中的重要性，并证明了雌激素对免疫细胞中miRNA表达的选择性调节。鉴于miRNAs在炎症调控中的作用，我们假设来自NZB/W雌性小鼠的浆细胞样树突状细胞(PDCs)和系膜细胞在肾炎的发生和发展中将显示出改变的miRNA图谱，并且用于SLE治疗的免疫抑制剂在一定程度上通过改变miRNA图谱来纠正疾病。我们的研究将：1.确定新鲜纯化的NZB/W小鼠肾小球系膜细胞和pDC的miRNA表达是否与疾病进展相关或预测疾病进展。2.将miRNA表达的变化与肾脏和脾的病理变化相关联，以详细说明miRNA的表达如何与疾病活动平行。此外，这些研究将测试改变特定的miRNA水平是否会改变疾病中诱导的炎症介质。3.明确三种狼疮疗法对NZB/W病小鼠肾小球系膜细胞和pDC中miRNA表达的影响机制。这些研究将表明，免疫调节剂改变疾病是否会导致miRNA表达模式的变化。我们组建了一支由Reilly博士领导的独特且高素质的研究团队，Reilly博士在肾炎动物模型和系膜细胞病理生理学方面拥有丰富的专业知识。艾哈迈德和戴博士在miRNAs方面拥有广泛的专业知识。考德尔博士是一名病理学家，擅长确定活体研究中器官和组织的受累程度。我们团队的每个成员都是高素质的，拥有独特的技能，这将使我们能够为miRNAs在狼疮性肾炎的系膜细胞和树突状细胞功能中的作用提供直接的科学支持。这些研究可能提供直接证据表明，在狼疮性肾炎的发病和传播过程中，肾小球系膜细胞和pDC中miRNA的水平发生了改变，并且在狼疮性肾炎的发生和传播中起着重要作用。此外，这些研究将展示对miRNAs影响疾病的途径的机械性洞察。这些目标的完成将提供对miRNA表达谱在PDCs和系膜细胞中SLE发展过程中作用的全面了解。我们将定义用几种常见狼疮疗法之一治疗后靶组织中miRNA表达谱的变化，并详细说明这些化合物减轻疾病的机制方法。完成这些目标可以提供一个新的目标，通过它可以减轻系统性红斑狼疮。

DESCRIPTION (provided by applicant): Extensive analysis of both genetics and environmental pathogens of systemic lupus erythematosus (SLE) has yet to reveal a common mechanism for the initiation of disease. The recent discovery of microRNAs (miRNAs) has initiated a flurry of investigations into how miRNAs may regulate gene expression. Substantial evidence exists that the miRNA system contributes to the regulation of a wide variety of normal cellular functions and pathologies. We have recently demonstrated the importance of miRNAs in immune cells and have shown the selective regulation of miRNA expression in immune cells by estrogen. Given the role of miRNAs in the regulation of inflammation, we hypothesize that plasmacytoid dendritic cells (pDCs) and mesangial cells from NZB/W female mice will show an altered miRNA profile in the initiation and progression of glomerulonephritis and that immunosuppressive agents used in the therapeutic management of SLE act to correct disease, in part, by altering miRNA profiles. Our studies will: 1. Determine if miRNA expression from freshly purified mesangial cells and pDCs from NZB/W mice correlates or predicts the development of disease progression. 2. Correlate the changes in miRNA expression to pathological changes in the kidney and spleen to detail how miRNA expression parallels disease activity. Furthermore, these studies will test if modifying specific miRNA levels alters inflammatory mediators induced in disease. 3. Define the mechanism of three lupus therapeutics on miRNA expression in mesangial cells and pDCs in diseased NZB/W mice. These studies will show if altering disease by immune modulators induces changes in miRNA expression patterns. We have assembled a unique and highly qualified team of investigators lead by Dr. Reilly, who has extensive expertise in animal models of nephritis and mesangial cell pathophysiology. Drs. Ahmed and Dai have extensive expertise in miRNAs. Dr. Caudell is a pathologist with expertise in defining the extent of organ and tissue involvement in in vivo studies. Each member of our team is highly qualified and possesses unique skills that will enable us to provide direct scientific support of the role of miRNAs in mesangial cell and dendritic cell function in lupus nephritis. These studies could provide direct evidence that miRNA levels are altered in mesangial cells and pDCs and play a significant role in the initiation and propagation of lupus nephritis. Additionally, these studies will show mechanistic insight into the pathways by which miRNAs influence disease. Completion of these aims will provide comprehensive understanding of the role of miRNA expression profiles in the development of SLE in pDCs and mesangial cells. We will define the changes in miRNA expression profiles in target tissues after treatment with one of several common lupus therapeutics and detail a mechanistic approach by which these compounds act to mitigate disease. Completion of these aims could provide a novel target by which SLE may be mitigated.