Idiopathic Pulmonary Fibrosis, or IPF, is a terminal disease affecting as many as 500,000 Americans with no FDA-approved therapies capable of stopping disease progression. The disease is characterized by excessive assembly of extracellular matrix (ECM) by activated fibroblasts termed `myofibroblasts'. Recently, studies have demonstrated that tissue mechanics, specifically tissue stiffness resulting from myofibroblasts assembly of ECM and contraction, is capable of driving the differentiation of myofibroblasts and thus disease progression. In short, myofibroblasts are capable of recruiting more myofibroblasts leading to a disease that progresses unchecked. Despite these recent findings we still do not understand how the process is initiated, nor do we have any therapies that effective halt disease progression. Basic molecular mechanisms for how cells sense this stiffness (mechano-sensing) have, however, been developed and identified. In this project we are harnessing the same cellular mechanisms that allow them to sense the increased stiffness toward the development of technology for delivering local, scar-directed therapy with the goal of treating and curing pulmonary fibrosis directly. This approach leverages years of scientific insight into the basis for mechanical sensing by cells and co-opts naturally occurring paradigms to turn the disease state against itself.

Public Health Relevance

Pulmonary fibrosis kills 40,000 Americans each year, the same number as breast cancer, and the only cure is lung transplantation. In pulmonary fibrosis, the lung becomes scarred and stiff. In this proposal we are using the body's natural ability to sense stiffness to enable cell-directed treatment/cure for fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL132585-03
Application #
9326335
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lin, Sara
Project Start
2015-09-07
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
University-Wide
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Fiore, Vincent F; Wong, Simon S; Tran, Coleen et al. (2018) ?v?3 Integrin drives fibroblast contraction and strain stiffening of soft provisional matrix during progressive fibrosis. JCI Insight 3:
Yamauchi, Mitsuo; Barker, Thomas H; Gibbons, Don L et al. (2018) The fibrotic tumor stroma. J Clin Invest 128:16-25
Chambers, Dwight M; Moretti, Leandro; Zhang, Jennifer J et al. (2018) LEM domain-containing protein 3 antagonizes TGF?-SMAD2/3 signaling in a stiffness-dependent manner in both the nucleus and cytosol. J Biol Chem 293:15867-15886
Cao, Lizhi; Nicosia, John; Larouche, Jacqueline et al. (2017) Detection of an Integrin-Binding Mechanoswitch within Fibronectin during Tissue Formation and Fibrosis. ACS Nano 11:7110-7117