Idiopathic pulmonary fibrosis (IPF) is one ofthe most pernicious forms of lung fibrogenesis and currently has no clearly effective treatments. Whereas the etiology of IPF remains enigmatic, there is a plenty of evidence showing dysregulated fibrogenesis, differentiation, contractility and migration of pulmonary fibroblasts from IPF lungs. However, the role of miRNAs in regulation of such aberrant activities in IPF fibroblasts (IPF-Fbs)is unknown. In our preliminary studies, we found that the expression of miR-31 is downregulated in the lungs of mice with bleomycin induced lung fibrosis. Target predictions demonstrate that miR-31 regulates the expression of integrin alphas and RhoA. These proteins are critical regulators of fibrogenesis, differentiation, contractility and migration of pulmonary myofibroblasts. This information, together with our preliminary data, suggests that miR-31 may play an important role in initiation and progression of IPF. Therefore, miR-31 appears to be a potential target for developing novel therapeutics to treat IPF. Our preliminary data showing that introduction of miR-31 mimics diminishes the severity of bleomycin induced lung fibrosis lend a strong support to this hypothesis. In this proposal, we aim to;determine the transcriptional and epigenetic mechanisms by which miR-31 is downregulated in IPF-Fbs;determine if miR-31 targets RhoA and integrin alphas, and thereby regulating the contractile, migratory, and fibrogenic activities of IPF-Fbs;determine if reconstitution of pulmonary miR-31 through intra-tracheal or intra-pleural delivery demonstrates therapeutic potentials in treating lung fibrosis in mouse models;determine if miR-31 inhibits PMC-myofibroblast differentiation/activation, if miR-31 expression is regulated by Src kinase signaling pathways, and if the antifibrogenic activity of miR-31 is mediated by N0X4 in IPF-Fbs.
The studies proposed in this application should not only improve the understanding ofthe role of miR-31 in the pathogenesis of IPF, but also provide solid foundation for moving miR-31 therapeutics to clinical trials in treating this devastating disease.
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