MicroRNA expression in the NZB/W lupus mouse

描述（由申请人提供）：对系统性红斑狼疮（SLE）的遗传学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如何调节基因表达的研究。大量证据表明，miRNA系统有助于调节多种正常细胞功能和病理。我们最近证明了miRNA在免疫细胞中的重要性，并显示了雌激素对免疫细胞中miRNA表达的选择性调节。鉴于miRNA在炎症调节中的作用，我们假设NZB/W雌性小鼠的浆细胞样树突状细胞（pDC）和系膜细胞在肾小球肾炎的发生和进展中显示出改变的miRNA谱，并且用于SLE治疗管理的免疫抑制剂部分通过改变miRNA谱来纠正疾病。我们的研究将：1。确定来自NZB/W小鼠的新鲜纯化的肾小球系膜细胞和pDC的miRNA表达是否与疾病进展的发生相关或预测疾病进展的发生。 2.将miRNA表达的变化与肾脏和脾脏的病理变化相关联，以详细说明miRNA表达如何与疾病活动性平行。此外，这些研究将测试是否修改特定的miRNA水平改变疾病中诱导的炎症介质。 3.明确三种狼疮治疗剂对患病NZB/W小鼠系膜细胞和pDC中miRNA表达的机制。这些研究将表明，通过免疫调节剂改变疾病是否会引起miRNA表达模式的变化。我们已经组建了一支由Reilly博士领导的独特且高素质的研究团队，他在肾炎和系膜细胞病理生理学的动物模型方面具有广泛的专业知识。Ahmed和Dai博士在miRNAs方面拥有丰富的专业知识。Caudell博士是一位病理学家，擅长定义体内研究中器官和组织的参与程度。我们团队的每一位成员都是高素质的，并拥有独特的技能，这将使我们能够为miRNAs在狼疮肾炎中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。这些研究可以提供直接的证据表明，肾小球系膜细胞和pDC中的miRNA水平改变，并在狼疮肾炎的发生和传播中发挥重要作用。此外，这些研究将揭示miRNAs影响疾病的机制。这些目标的完成将提供对miRNA表达谱在pDCs和系膜细胞中SLE发展中的作用的全面理解。我们将定义用几种常见的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用于减轻疾病的机制方法。这些目标的完成可以提供一个新的目标，通过它可以减轻SLE。

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.