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. In the current research proposal we hypothesize that an emergent fibroblast subpopulation displays dysregulated mechanotransductive phenotypes due to an inability of these cells to sense the stiffness of their environment. These fibroblasts are thus capable of assembling and contracting the ECM, like myofibroblasts, even in soft environments, thus skewing the matrix from normal to pro-fibrotic. We propose to define the aberrant phenotypes, identify the molecular mechanism, and propose a novel approach toward the normalization of aberrant fibroblast mechanotransduction. We will use a host of cell sources from human to mouse, model ECMs from purely synthetic to human disease-derived, and animal models of disease along with advanced biophysical and cell biological assays to complete the project. The research proposed in this application is significant not only in terms of its potential impact on the clinical diagnosis and treatment of IPF, but also in its impact on our understanding of the mechanistic underpinnings of the transition from normal wound healing to fibrotic progression within the lung.

Public Health Relevance

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. In this application we explore a new hypothesis explaining how the disease is initiated and pose a novel therapeutic strategy toward stopping disease progression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127283-02
Application #
9033145
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2015-04-01
Project End
2019-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30318
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
Barker, Thomas H; Engler, Adam J (2017) The provisional matrix: setting the stage for tissue repair outcomes. Matrix Biol 60-61:1-4
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
Brown, Ashley C; Dysart, Marilyn M; Clarke, Kimberly C et al. (2015) Integrin ?3?1 Binding to Fibronectin Is Dependent on the Ninth Type III Repeat. J Biol Chem 290:25534-47
Bachman, Haylee; Nicosia, John; Dysart, Marilyn et al. (2015) Utilizing Fibronectin Integrin-Binding Specificity to Control Cellular Responses. Adv Wound Care (New Rochelle) 4:501-511
Fiore, Vincent F; Strane, Patrick W; Bryksin, Anton V et al. (2015) Conformational coupling of integrin and Thy-1 regulates Fyn priming and fibroblast mechanotransduction. J Cell Biol 211:173-90