Idiopathic Pulmonary Fibrosis (IPF), a chronic interstitial fibrotic lung disease, affects 200,000 Americans per year with a median survival of approximately 3 years. There is no effective therapy except lung transplantation. The pathological hallmark of IPF is the formation of fibroblastic foci consisting of a large number of activated and proliferated fibroblasts (myofibroblasts). These cells deposit excessive extracellular matrix, resulting in pulmonary fibrosis. Residential fibroblast proliferation and activation is thought to be one of the major contributors to the pathogenesis of IPF. However, signaling pathways and their regulators leading to fibroblast expansion and activation are not completely understood. Thus, there is a critical need to understand molecular mechanisms of fibroblast proliferation and activation in IPF. The PI's long-term goal is to elucidate the pathogenesis of IPF and thus advance development of effective pharmacological therapy. The objective of the current application is to understand microRNA regulation of the signaling pathways involved in fibroblast proliferation and activation in IPF. Although it is appreciated tha canonical Wnt/?-catenin and transforming growth factor-? (TGF-?) signaling pathways are involved in IPF, little is known regarding the non-canonical Wnt/Nuclear factor of activated T-cells (NFAT) signaling in IPF. MicroRNAs, small non-coding RNAs, are increasingly recognized for their importance in regulating signaling pathways. However, which microRNAs and how they regulate the signaling pathways in IPF are still unclear. Preliminary studies have demonstrated that miR-101 is down-regulated in the lungs of IPF patients, that the activation of Wnt/NFAT signaling stimulates fibroblast proliferation, and that miR-101 inhibits Wnt/NFAT-induced fibroblast proliferation and TGF-?- stimulated fibroblast activation by targeting their cell membrane receptors. The overall hypothesis of this proposal is that the down-regulation of miR-101 contributes to pulmonary fibrosis by promoting residential fibroblast proliferation through Wnt/NFAT signaling, and stimulating fibroblast activation through TGF-? signaling.
Aim I will determine the transcriptional regulation of miR-101 by TGF-? signaling.
Aim II will delineate the mechanisms of miR-101-mediated inhibition of fibroblast proliferation and activation.
Aim III will evaluate the effects of miR-101 on pulmonary fibrosis in vivo. Expected outcomes are establishment of mechanisms for the down-regulation of miR-101 in IPF, identification of miR-101 and its targets as critical factors for fibroblast proliferation and activation, and a foundatin for developing miR-101 therapy for IPF.
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