Mechanotransduction regulation of cellular metabolism in pulmonary fibrosis

About This Grant

PROJECT SUMMARY Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring disease with limited therapeutic options. Fibrotic lung diseases are characterized by an accumulation of excess extracellular matrix (ECM), contributing to the destruction of lung architecture, inability to perform gas exchange, and even death. My mentor published pioneering work that IPF patients have abnormally high levels of lactate in their lungs. Lactate in turn decreases the local pH, which activates latent TGFβ, resulting in a pro-fibrotic feed-forward loop that drives fibrosis and dysregulated metabolism. We and others have demonstrated that increased tissue stiffness in lung fibrosis also drives fibroblast differentiation, expression of matrix proteins, and cross-linking, resulting in further increases in tissue stiffness. While tissue stiffness and altered lactate metabolism are independently recognized as pathogenic pathways and potential therapeutic targets, I have now identified the mechanoreceptor Piezo2 as a potential link between altered tissue mechanics and aberrant metabolism. In this revised project application, I will use patient-derived non-fibrotic and IPF lung fibroblasts to characterize the mechanism by which Piezo2 drives metabolic adaptations in response to increased matrix stiffness, and how these metabolic adaptations contribute to a feed-forward loop that drives fibrosis. I will also use well-characterized pre-clinical mouse models of pulmonary fibrosis to investigate the role of Piezo2 in vivo using genetic knockdown and pharmaceutical inhibition approaches. To further support the clinical relevance of my results, the metabolic adaptations identified in the cell culture and mouse models will be compared with my new evidence of metabolic disruptions in the lungs of IPF patients obtained by metabolomics analysis of exhaled breath condensate. This project will support my career goal to transition to a tenure-track faculty position as an independent investigator. To complete my technical training needs for this project, I will work with my co-mentor Dr. L. Ashley Cowart to participate in extensive hands-on training in metabolomics data analysis, as well as attend training courses at the highly regarded West Coast Metabolomics Center at UC Davis. My co-mentor Dr. Patricia Sime will guide me in my professional development as an independent scientist by providing additional training opportunities in translational research, grant writing and scientific communication, lab management and administration, teaching, and mentoring others. I have established a strong mentor committee and strong relationships with internal and external collaborators. Virginia Commonwealth University is a highly productive scientific environment and is very supportive of my development as an independent scientist. My training and research experience under this career development award will yield novel insights into the pathogenic mechanisms of pulmonary fibrosis, giving me foundational skills and my own research project to carry me into independence.