The origins of lung disease often begin during development. Unraveling the complex mechanisms that regulate development is essential for understanding the pathogenesis of developmental, genetic and acquired lung disease. This proposal is focused around the mechanisms by which Fibroblast Growth Factor 9 (FGF9) signaling regulates lung development. FGF9 is made in lung epithelium and mesothelium and has a major role in regulating mesenchyme and secondary direct and indirect roles in the regulation of lung epithelium. We have identified a feed-forward regulatory network that involves mesenchymal FGF receptor (FGFR) and Wnt/-catenin signaling. In data published since the first submission of this proposal, we showed that both FGF and Wnt/-catenin pathways function in vivo to suppress Noggin. This finding couples mesenchymal FGF-Wnt/-catenin signaling with Bmp pathways that regulate epithelial growth and differentiation. Another means to gain insight into developmental mechanisms is to study the pathogenesis of cancer, a disease which often co-opts embryonic regulatory mechanisms. A potential link between FGF9 signaling in lung mesenchyme and human lung disease involves the heritable pediatric lung cancer syndrome, pleuropulmonary blastoma (PPB). PPB is interesting because it arises from embryonic uncommitted lung mesenchymal cells. Mouse embryonic lung that was induced to overexpress FGF9 develops mesenchymal hyperplasia with histology that mimics that of type I PPB, suggesting that FGF9 might be involved in the pathogenesis of PPB. The genetic origins of PPB were mapped to loss-of-function mutations in the microRNA (miRNA) processing gene, DICER1. Preliminary and published data shows that Dicer1 ablation in developing lung epithelium mimics the early cystic stage of PPB. Immunohistochemical studies of PPB tumors with mutations in DICER1 often show decreased DICER1 expression in lung epithelium. These observations suggest a model to explain the pathogenesis of PPB in which decreased epithelial miRNAs processed by DICER1 results in overexpression of an epithelial gene(s) and production of a factor(s) that stimulates the proliferation of adjacent mesenchyme, predisposing the mesenchyme to neoplastic transformation. Preliminary data provides evidence that implicates epithelial-derived FGF9 in mediating some of the pathogenic consequences of loss-of-function mutations in DICER1. We hypothesize that Fgf9 may be a major pathogenic gene that is directly regulated by DICER1-mediated miRNA pathways. In this proposal, we will: 1) Elucidate the mechanism by which mesenchymal FGF and Wnt/ -catenin signaling regulates Noggin expression and activity of the BMP pathway; 2) Test the hypothesis that FGF9 is a pathogenic mediator of mesenchymal hyperplasia in a mouse model for PPB; and 3) Compare the lung mesenchymal transcriptional landscape regulated by FGF9 and Wnt/-catenin signaling and by Fgf9 and Dicer1 mouse models for PPB with early stage human PPB.
Lung disease is the fourth leading cause of death and disability in the United States. The etiology of lung disease often begins during embryonic development or early in life. To understand the pathogenesis of genetic, developmental, and acquired lung disease, to develop diagnostic criteria for these diseases, and to develop rational therapies, knowledge of the molecular, cellular and developmental mechanisms that regulate lung development is necessary. This proposal will focus on developmental mechanisms that involve Fibroblast Growth Factor 9, a signaling molecule that is essential for lung development and implicated as a pathogenic mediator of pleuropulmonary blastoma, a rare pediatric lung cancer.
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