Sarah Dabaja
Research Mentor: Thomas Sisson
Mentor Department: Internal Medicine, Medicine
Author(s): Sarah Dabaja, Gabrielle Onishi, Natayla Subbotina, Thomas Sisson, MD
Session: Session 7 (4:00 PM – 4:50 PM)
Presentation Type: Poster 41
Abstract
Pulmonary fibrosis is a fatal chronic lung disease that is characterized by a dysregulated healing response to repetitive injury. Our project is centered around defining the role of plasminogen activator inhibitor-1 (PAI-1) in the development of lung fibrosis. We have discovered a novel interaction between PAI-1 and SorLA that is required for fibrosis, and we are now investigating how the interaction between these proteins shapes cell function. We are investigating the therapeutic potential of MDI, which has been shown to reduce the fibrotic phenotype in both fibroblast cells and mouse models. However, the molecular mechanisms underlying this effect remain unclear. We hypothesize that the PAI-1-SorLA interaction promotes fibroblasts to differentiate into profibrotic myofibroblasts and that this fibroblast activation occurs through a PAI-1-mediated upregulation of mTOR signalling. We also hypothesize that MDI prevents fibrosis thereby preventing fibroblast differentiation into profibrotic myofibroblasts through decreased mTOR signaling. To test this hypothesis, we will be using fibroblast cell culture stimulated with a profibrotic growth factor with and without a PAI-1 inhibitor. We will employ western blotting to assess changes in protein levels and changes in phosphorylation of mTOR protein targets. This method will allow us to quantify the different signaling across the cell populations and test for a functional impact. Understanding how PAI-1 increases fibrosis is extremely relevant. By defining these pathways, this research will advance the field of chronic lung disease and may identify novel therapeutic strategies that will benefit the patients that deal with pulmonary fibrosis.
