Targeting Isoform-specific FGFR Signaling in Idiopathic Pulmonary Fibrosis

ABSTRACT Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease predominantly affecting older adults, with most diagnoses occurring in individuals over 65. Treatment options for IPF are limited, and existing medications focus on slowing disease progression rather than providing a cure. This underscores the need for detailed studies of the disease's root causes and the development of strategies to target specific pathways for safe and effective treatment. The fibroblast growth factor receptor (FGFR) signaling pathway is implicated in the pathogenesis of IPF; however, the exact mechanism by which FGFR signaling contributes to pulmonary fibrosis remains unclear. We hypothesize that the activities of the mesenchymal c-isoform and the epithelial b-isoform of FGFR play distinct roles in the pathogenesis of pulmonary fibrosis and that modulating the isoform-specific activities of FGFR could potentially provide an effective means to alleviate pulmonary fibrosis. The aims of this proposal seek to address this overall hypothesis by (1) conducting comprehensive in vitro studies of FGFR isoform-specific signalings in primary lung cells, and (2) establishing the effects of modulating FGFR isoform- specific signaling in an animal model of pulmonary fibrosis. The outcome of the proposed studies will provide the enhanced understanding of FGFR signaling in pulmonary fibrosis and offer novel therapeutic avenues for the treatment of IPF.