Grant: Operating Grant

Organ fibrosis is an aberrant healing process or a failed attempt to repair tissue injury, which occurs as a consequence of many common disease conditions, such as long-lasting inflammation, diabetes, hypertension and drug abuse. Organ fibrosis is a devastating and ultimately lethal condition that characterizes a large variety of pathologies, including many chronic lung and kidney diseases and liver cirrhosis. It is estimated that 45% of all deaths in the western world can be attributed to some form of chronic fibrotic disease. A major common factor in these disease states is the formation and activation of a motile and aggressive muscle-like cell type, the myofibroblast (MF), which produces a tissue-destroying matrix. Recent studies from several laboratories including our own have demonstrated that MFs can derive from injured epithelial cells, through a process called epithelial-mesenchymal transition (EMT). It is known that the disruption of intercellular contact is key trigger for EMT and thereby fibrosis, but the underlying mechanisms are not well defined. Our previous research has identified new cell fate-determining changes in the localization and expression of key proteins during EMT. We would like to know how the injury of cell-cell contacts impacts on these newly recognized mechanisms, i.e. how disruption of the coupling between cells facilitates the conversion of tight epithelial layers to loosely organized, contractile, scar-forming and destructive MFs. We would also like to test whether these new molecular mechanisms contribute to the development of disease in animal models of lung fibrosis or in patients with idiopathic pulmonary fibrosis. We will use a variety of cell and molecular biology techniques, live video microscopy and histology to address these important questions. We hope to gain key insights into the basic mechanisms underlying organ fibrosis, and identify therapeutic targets to halt or lessen this fatal disease.