A novel microRNA in pulmonary fibrosis

Lurie Children'S Hospital Of Chicago, Chicago IL

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Abstract

? DESCRIPTION (provided by applicant): Chronic diseases of the lung including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF) are a major health burden, almost always resulting in respiratory failure. In all cases, disease progression involves repeated cycles of inflammation, followed by epithelial injury and repair, which in turn, causes scarring and fibrosis of the epithelium. Epithelial remodeling and fibrosis are well- recognized processes, yet knowledge of specific genes and pathways that govern these changes is currently lacking. MicroRNAs (miRNAs, miRs), which are small RNAs responsible for repressive gene regulation, are compelling candidates for modulating lung epithelial repair in disease. A single miRNA is capable of regulating the expression of hundreds of genes simultaneously. These target genes often cluster within similar signaling or functional pathways, highlighting the importance of miRNAs in regulating global biological processes. The potential for miRNAs to impact the progression of lung fibrosis is poorly studied, and yet miRNAs may be critical components underlying pathological mechanisms. Environmental factors are known to influence development of COPD and IPF; however, lung disease progression is not well correlated with exposure to these insults. Likewise, severity of lung disease in CF cannot be predicted based on the causal CF mutation alone. These observations suggest that many modifying genes and non-genetic factors converge to impact the process of pulmonary fibrosis. One such modifier, transforming growth factor beta (TGF-ß), is well documented to play a critical role in cell proliferation and differentiation to control lung health Canonical TGF-ß signaling is intimately involved in regulating fibrotic responses to lung injury, and polymorphic variants in TGF-ß1 are known to modify CF lung disease severity. The essential contribution of microRNAs in many biological processes underpins our objective to study the role of miR-1343, which we show to significantly repress TGF-ß signaling in lung epithelial cells and fibroblasts. There is currently no published information on miR-1343, though our data show that this miRNA is expressed in a variety of lung-derived primary cells and cell lines. Because of its role in TGF-ß signaling, our goal is to investigate mechanisms of miR-1343-mediated TGF-ß repression and to analyze how its expression can modify severity of lung disease. To this end, we will test the hypothesis that that miR-1343 in the lung acts as a phenotypic modifier of pulmonary disease by controlling the expression of functionally important target genes in respiratory tract epithelium and fibroblasts. Experiments in the first aim will see to elucidate the mechanism by which miR-1343 can modify TGF-ß signaling and pulmonary fibrosis. In the second aim, genetic variants that influence miR-1343 expression in the lung and how these variants are associated with lung disease severity will be investigated. This research will be of fundamental importance to identify novel biomarkers and therapeutic strategies for the treatment of multiple chronic lung diseases.