Grant: Operating Grant

Organ fibrosis is a chronic scarring process due to cycles of tissue injury and failed repair. It is estimated that 45% of all deaths in the western world can be attributed to some form of chronic fibrotic disease, which can develop as a consequence of chronic inflammation, diabetes, hypertension, drug abuse and environmental toxins. It is the major and death-inducing mechanism in many chronic lung and kidney diseases and liver cirrhosis. Stunningly, the overall life expectancy of people with progressive fibrosis is worse than that of the cancer patients. Currently there is no cure to halt or reverse the process. A main culprit of the disease is a matrix producing muscle-like cell type the so called myofibroblast. These cells can develop from epithelial cells that, in a disease-inducing environment, undergo epithelial-myofibroblast transition. In order to lessen fibrotic processes, we have to understand how myofibrobalst are generated. Our previous work has shown that growth factors and injury to the cell contacts act in synergy to provoke the transformation of epithelial cells to myofibroblasts. Recently we have found novel molecular and cellular mechanisms that involve changes in the cell skeleton and the cell's sensory antenna, the primary cilium. However currently we do not understand how these act together to induce the deleterious process. This proposal aims to clarify how the cell skeleton, the primary cilium and fibrosis-inducing growth factors bring about major changes in cell fate. We will use an array of cell and molecular biology techniques, including changes in gene expression and life cell imaging analysis on cellular models and cells from patients with fibrosis. The gained knowledge will help us understand the fundamental mechanisms underlying this devastating disease entity define targets for therapeutic interventions.