Idiopathic Pulmonary Fibrosis (IPF) is a relentless and devastating disease leading ultimately to breathlessness, respiratory failure, and death within three years from the time of diagnosis. These grim facts emphasize that it is imperative to understand how IPF develops in order to design novel and rational therapeutics for this disease. We have found that expression levels of the transcription factor twist1 are associated with lung function in IPF. Furthermore, our data suggest that high and low expression of twist1 may predict distinct manifestations of lung fibrosis. Low twist1 expression is associated with increased inflammation, and high twist1 is associated with more prominent scarring. Thus, the study of twist1 in IPF is critical: the knowledge gained from the study of twist1 has the clear potential to impact the clinical care of IPF patients in very meaningful and profound ways: the study of twist1 may uncover biomarkers to identify IPF patients at the greatest risk of death and who need to be prioritized for lung transplant.
The first aim of our study is to determine if low levels of twist1 in fibroblasts will promote pulmonary fibrosis by regulating the pro-inflammatory molecule CXCL12.
The second aim proposes to study if high levels of twist1 will promote fibrosis through a different mechanism: by facilitating the survival of fibroblasts through two novel effector molecules, survivin and miR-214. We will employ human tissues and cells as well as unique transgenic animals to test our hypotheses. Hence, the goal of this application is to elucidate a new molecular model where expression of twist1 results in pathologic signaling in the lung leading to fibrosis. Ultimately, we aim to uncover unique targets to treat IPF.

Public Health Relevance

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal scarring of the lung. Lung transplantation may be the only therapeutic option. This study is designed to test the role of twist1 in experimental pulmonary fibrosis. We hypothesize that twist1 contributes to the distinct presentations of IPF in different patients and that twist1 may be a potential therapeutic target to treat this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126990-05
Application #
9655351
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Craig, Matt
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15260
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