Targeting Lung Fibrosis with Epigenetic Therapy

PROJECT SUMMARY Pulmonary fibrosis is a complex disease that limits lung function through development of collagen-rich scar tissue. Although there are currently two FDA-approved therapies for fibrosis patients, these drugs are capable of extending life only months and do not reverse the progression of the disease. The research described in this proposal would build upon evidence that reprogramming cellular fate through modulation of the epigenetic enzyme EZH2 can ameliorate several phenotypes of pulmonary fibrosis, including aberrant alveolar cell fate, endothelial to mesenchymal transition and pro-fibrotic cytokine signaling mediated by myeloid cells. Specifically, the aims will test if the FDA-approved EZH2 inhibitor, tazemetostat, will allow for prevention or reversion of these cellular phenotypes. The model systems to be used include both human and mouse organotypic cell cultures and two established in vivo models of pulmonary fibrosis, namely lung instillation of the chemotherapy bleomycin or adeno-associated virus (AAV) expressing TGFβ. For Aim 1, we will quantify the extent of aberrant basaloid/alveolar transition cells in lung epithelial cultures that are depleted for EZH2 activity genetically or pharmacologically, and assess rescue of this phenotype by deletion of the transcription factor FOXP2. Patient tissues will be used to understand if EZH2 activity is high in aberrant basaloid/alveolar transition cells in vivo. Co-cultures of endothelial cells with both epithelial and myeloid cell populations will allow for recapitulation and examination of paracrine signaling that may control both alveolar fate and endothelial to mesenchymal transition. In Aim 2 in vivo lung injury models will be used to examine both prevention and treatment of lung fibrosis, and to characterize specific changes to the epithelial, endothelial and myeloid cell populations driven by EZH2 inhibition. Lung function testing, histology, and flow cytometry will be used to characterize the lung phenotypes. We expect that this research could validate the use of EZH2 inhibition as a treatment for pulmonary fibrosis, and will expand our knowledge in the field of lung epigenetics. 1