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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL114470-02
Application #
8735177
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Eu, Jerry Pc
Project Start
2013-09-16
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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