Fibrosis involving the airways, vasculature, alveoli, and pleura is seen, to varying degrees, in a number of clinical syndromes, including asthma, subphenotypes of chronic obstructive pulmonary disease, pulmonary hypertension, and idiopathic pulmonary fibrosis (IPF). Currently, there are no FDA-approved anti-fibrotic therapies for any of these disorders in the United States. A common feature of fibrosis in these clinical-pathological contexts is the activation of tissue myofibroblasts. In this translational Program Project Grant (tPPG) application, we propose to develop pharmacologic strategies and agents targeting the myofibroblast in the most enigmatic and fatal form of pulmonary fibrosis, IPF. Current paradigms of the origin(s) of myofibroblasts posit that these fibrogenic cells derive from resident mesenchymal progenitors, alveolar epithelial cells (via epithelial-to-mesenchymal transition), or circulating fibrocytes. In this tPPG, we will investigate the role of pleural mesothelial cells (PMCs) as progenitors of activated lung myofibroblasts (Project 1). While myofibroblasts are widely considered a specific subset of a heterogeneous fibroblast population, in reality, they themselves manifest a number of different phenotypes, including migration/invasion, proliferation, contractility and apoptosis-resistance. Maintenance of myofibroblast differentiation and activation is governed by extracellular factors (matrix stiffness activation of latent TGF-), cell adhesion/contractile factors (integrins, RhoA), and intracellular signaling cascades (SMAD2/3, Wilm's tumor-1) that activate or repress fibrogenic gene expression. These interacting pathways are controlled by the anti-fibrotic micro-RNA, miR-31, and the pro-fibrotic oxidant-generating enzyme, NADPH oxidase-4 (NOX4). This tPPG will establish proof-of-concept and provide essential pre-clinical data supporting the therapeutic efficacy of reconstituting miR-31 and/or inhibiting the expression/activation of N0X4 in experimental animal models and in cell/tissues of patients with IPF, leading rapidly to Phase l/ll clinical trials for this recalcitrant lung disease.
IPF is fatal lung disorder for which no U.S. FDA-approved drugs currently exist. This project will lead to the development of novel anti-fibrotic therapies, which if proven effective, may also be tested in other clinical disorders characterized by myofibroblast activation and progressive fibrosis.
| Chanda, Diptiman; Otoupalova, Eva; Smith, Samuel R et al. (2018) Developmental pathways in the pathogenesis of lung fibrosis. Mol Aspects Med : |
| Qu, Jing; Zhu, Lanyan; Zhou, Zijing et al. (2018) Reversing Mechanoinductive DSP Expression by CRISPR/dCas9-mediated Epigenome Editing. Am J Respir Crit Care Med 198:599-609 |
| Thannickal, Victor J; Antony, Veena B (2018) Is personalized medicine a realistic goal in idiopathic pulmonary fibrosis? Expert Rev Respir Med 12:441-443 |
| Rangarajan, Sunad; Bone, Nathaniel B; Zmijewska, Anna A et al. (2018) Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 24:1121-1127 |
| Zhou, Yong; Horowitz, Jeffrey C; Naba, Alexandra et al. (2018) Extracellular matrix in lung development, homeostasis and disease. Matrix Biol 73:77-104 |
| Cui, Huachun; Xie, Na; Banerjee, Sami et al. (2018) Impairment of Fatty Acid Oxidation in Alveolar Epithelial Cells Mediates Acute Lung Injury. Am J Respir Cell Mol Biol : |
| Hough, Kenneth P; Trevor, Jennifer L; Strenkowski, John G et al. (2018) Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol 18:54-64 |
| Bernard, Karen; Logsdon, Naomi J; Benavides, Gloria A et al. (2018) Glutaminolysis is required for transforming growth factor-?1-induced myofibroblast differentiation and activation. J Biol Chem 293:1218-1228 |
| Ge, Jing; Cui, Huachun; Xie, Na et al. (2018) Glutaminolysis Promotes Collagen Translation and Stability via ?-Ketoglutarate-mediated mTOR Activation and Proline Hydroxylation. Am J Respir Cell Mol Biol 58:378-390 |
| Hough, Kenneth P; Wilson, Landon S; Trevor, Jennifer L et al. (2018) Unique Lipid Signatures of Extracellular Vesicles from the Airways of Asthmatics. Sci Rep 8:10340 |
Showing the most recent 10 out of 70 publications
