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.
Lupus is a chronic inflammatory disease of autoimmune etiology in which patients produce antibodies against their own nuclear components. MicroRNAs are short RNA molecules that serve as post-transcriptional regulators by partially binding to the 3'untranslated region of target messenger RNAs, inhibiting protein translation and therefore gene expression. Our research will show that microRNAs are differentially expressed in lupus mice and can be the targets of cyclophosphamide, hydroxychloroquine, and mycophenolate mofetil, three common lupus therapeutics.
