Alveolar epithelial cells (AEC) contribute to lung repair responses by proliferating, regulating matrix resorption, and presenting active TGF(1 to fibroblasts, promoting their conversion to myofibroblasts. AECs may also exercise their own plasticity to become fibroblast-like in their invasiveness and matrix production a process termed epithelial to mesenchymal-like transitions (EMT). While many lines of evidence link persistent active TGF(1 to the pathobiology of lung fibrosis, prolonged global inhibition of TGF(1 signaling is likely to have unacceptable toxicities. A more targeted therapeutic approach to blockade of TGF(1 signaling is needed. Recent findings identify a (1 integrin-dependent specific signaling pathway involving crosstalk between a tyrosine phosphorylated (-catenin (pY654) and Smad signaling that drives, and is required for, AEC EMT ex vivo and in vivo during fibrogenesis in mice. These observations lead to the hypothesis that dysregulated accumulation of nuclear pY654-(-catenin/pSmad2 complexes in AECs drives EMT, expands myofibroblasts, and results in progressive pulmonary fibrosis. This hypothesis is addressed in the application by a series of experiments designed to dissect and elucidate the key signaling events of EMT and myofibroblast expansion downstream of formation of (-catenin/pSmad2 complexes. It is postulated that pSmad2 functions as a key switch to either suppress EMT and fibrosis or, when complexed with pY654-(-catenin, switch on reprogramming leading to EMT. To test this hypothesis, mice with conditional deletion in vivo of the key components of the proposed signaling pathway will be used, along with a fate-mapping system to quantify EMT in vivo. Important gene targets of (-catenin/pSmad2 complexes in AECs and myofibroblasts will be defined through promoter analyses and direct DNA binding assays (chromatin immunoprecipitation). Biomarkers of the pathway driving EMT defined in mice will then be used to assess the activity of the (-catenin/pSmad2 pathway in human lungs. Collectively, these experiments should clarify important uncertainties regarding the role of EMT in pulmonary fibrosis, including Idiopathic Pulmonary Fibrosis (IPF). If the hypotheses prove largely correct, the studies should define a specific TGF(1-driven signaling pathway that could be quantified in IPF patients and serve as a basis for targeted therapy, avoiding the toxicities of prolonged global inhibition of TGF(1 signaling.

Public Health Relevance

There are currently no effective treatments to halt progression of lung scarification in patients with pulmonary fibrosis. The goal of this application is to delineate a specific set of signals that emanate from the prototypical wound repair cytokine, TGF(1, and drive pulmonary fibrosis. If successful, the studies should define a specific signaling pathway that could be quantified in Idiopathic Pulmonary Fibrosis patients and serve as a basis for targeted therapy, avoiding the expected toxicities of prolonged global inhibition of TGF(1 signaling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044712-23
Application #
8605207
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
1991-01-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
23
Fiscal Year
2014
Total Cost
$344,149
Indirect Cost
$121,399
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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