PAD4 Contributes to the Profibrotic Phenotype of Fibroblasts from Patients with IPF and Promotes Lung Fibrosis

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PROJECT SUMMARY/ABSTRACT The objective of this proposal is to investigate the molecular mechanisms underlying the development of pulmonary fibrosis and the profibrotic phenotype of pulmonary fibroblasts in fibrotic lung diseases like idiopathic pulmonary fibrosis (IPF). IPF is a devastating, chronic, progressive, fibrotic lung disease that leads to death in 3-5 years in the absence of lung transplantation. Although the disease is considered rare—affecting approxi- mately 100,000 people in the United States—the high cost of care and significant impact on quality and quantity of life imparts a significant burden. Importantly, the incidence of IPF is increasing for unclear reasons. Treatment options are limited to supportive care, lung transplantation, or medical therapies that do not resolve but rather slow the progression of disease. This limitation is in part due to an incomplete understanding of the pathophysi- ology underlying IPF. There is thus an urgent need to improve understanding of the cellular and molecular mech- anisms contributing to the pathogenesis of IPF in order to develop new therapeutic options. The proposed project will address this need through investigation of peptidylarginine deiminase 4 (PAD4), an enzyme that catalyzes the post-translational modification of peptidyl-arginine residues to peptidyl-citrulline and that has recently been implicated in the development of organ fibrosis in an aged animal model. Through gain- and loss-of-function experiments, PAD4’s contribution to the profibrotic phenotype of IPF fibroblasts will be determined. Moreover, through use of a small molecule inhibitor, the effect of PAD4 deficiency on the develop- ment of pulmonary fibrosis in a bleomycin mouse model and in ex vivo human precision-cut lung slices will be defined. By elucidating its role in the development of pulmonary fibrosis, this work will determine if PAD4 is a viable therapeutic target for fibrotic lung disease. This proposal describes a three-year research fellowship program that will allow the principle investigator to begin an academic research career in pulmonary disease. He will undertake this project within the Division of Pulmonary and Critical Care Medicine at Brigham and Women’s Hospital under the close mentorship of his sponsor Dr. Ivan Rosas, an expert in the field of interstitial lung disease and pre-clinical models of pulmonary fibrosis, and co-sponsor Dr. El-Chemaly, also an expert in the field of interstitial lung disease and in in vitro techniques for assessing fibrosis. The principle investigator will also benefit from the expertise of other highly accomplished members of his Scientific Advisory Committee and have access to the comprehensive intellectual and physical resources available within the Division and greater Harvard biomedical community. In addition to serving as a critical step in the principle investigator’s career development, this project will provide a basis for future research endeavors, as he advances from fellowship, to junior faculty, and, ultimately, to an independent NIH-funded investigator.