Research Project
10218249
Idiopathic pulmonary fibrosis (IPF) is a most enigmatic fatal lung disorder. Although significant progress has been made in our understanding of IPF pathogenesis, the molecular mechanisms underlying the pathophysiology of IPF remain poorly understood. Moreover, although two anti-fibrosis drugs, pirfenidone and nintedanib, have been approved by FDA for the treatment of IPF, the efficacy of these drugs for the later stages of the disease is uncertain and neither drug reduces IPF mortality (1-4). Based on the results from the Cycle I of this Translational Program Project (tPPG), we will, in this renewal tPPG, test a hypothesis that redox-metabolic control of myofibroblast activation, modulated by innate/adaptive immune mechanisms (alveolar macrophages and B-cells), leads to progressive fibrosis. Specifically, we will test the safety and efficacy of a small molecule inhibitor of NOX1/4 in a Phase IIb clinical trial (Project 1; Duncan, Project Leader) and explore the mechanisms by which NOX4 regulates pro-fibrotic metabolic programs in myo-Fbs (Project 2; Thannickal, Project Leader). Based on new convincing data, we will also investigate the role of NOX4 in regulating cellular metabolism and pro-fibrotic phenotypes of alveolar macrophages (Project 3; Carter, Project Leader) and the role of auto-Abs (B- cells) in regulating epigenetic control of pro-fibrotic genes in activated myo-Fbs (Project 4; Sanders, Project Leader). To aid in testing the hypothesis and developing the therapeutic drugs for IPF, the overall objective of the Animal Core is to provide centralized and standardized procedures for the animal studies proposed in Projects 2, 3, and 4. Specifically, the Core will provide two of the most commonly used murine lung fibrosis models, bleomycin-induced and asbestos-induced lung fibrosis models, for Project 2, 3, and 4 to test the therapeutic potential of GKT137831 for lung fibrosis and the underlying mechanism. The core will also provide standardized service for drug (GKT137931) delivery through oral gavage. Moreover, the Core will provide standardized technique service for the measurement of lung injury and fibrosis by micro CT image and mouse lung function by FlexiVent. Centralization and standardization of the procedures will lead to high quality, reproducible, and comparable results among individual projects, which are essential for the success of this tPPG.
