Targeting cell durotaxis as a novel therapeutic strategy for idiopathic pulmonary fibrosis

• Applicant: Dr. Ingo Ganzleben
• Subject Area: Cell Biology ; Pneumology, Thoracic Surgery
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490745655

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with minimal therapeutic options. Accordingly, new and effective therapies for IPF are desperately needed. Recruitment of pulmonary fibroblasts to sites of tissue injury and their subsequent activation into scar-forming myofibroblasts are critical steps in the development of lung fibrosis. Accordingly, therapeutic strategies aimed at targeting fibroblast chemotaxis have recently entered clinical trials for the treatment of IPF. However chemotaxis is notoriously redundant and chemokine receptors are shared by multiple cell types including fibroblasts and leukocytes, which might lead to unspecific off-target effects. Thus, further research is needed to develop a more safe and selective anti-fibrotic strategy targeting pathological cell recruitment. Our recent preliminary data suggest that fibroblasts, but not leukocytes, are potently recruited to areas of active fibrosis via "durotaxis”, a mechanism in which cells migrate up matrix´ stiffness gradients. Preliminary data in preclinical models suggest that fibroblast durotaxis may drive lung fibrosis development and progression in vivo, albeit direct imaging of durotaxis in vivo remains a major knowledge gap in the field due to technical challenges, as studying this process requires a combination of new and advanced imaging techniques. Within the proposed project, I will employ multiphoton microscopy (MPM) to visualize durotaxis-induced cell distribution and migration in the lung using ex vivo and in vivo fibrosis models. Finally, I will test the efficacy of a novel small molecule inhibitor targeting fibroblast durotaxis at inhibiting lung fibrosis in a preclinical mouse model. The experiments proposed in this application will provide new knowledge regarding the role of fibroblast durotaxis in the development and progression of lung fibrosis, and the potential efficacy of antidurotactic therapy for the treatment of lung fibrosis.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Benjamin D. Medoff