Controlling collagen deposition by fibroblasts in cutaneous fibrosis by targeting TANGO1 function

• Applicants: Professor Dr. Thomas Krieg; Professor Dr. Gerhard Sengle
• Subject Area: Dermatology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468236352

Fibrotic reactions can develop in almost any tissue and still represent a major cause of death and economic burden. They can occur as a consequence of chronic inflammatory processes and are characterized by excessive deposition of extracellular matrix (ECM) in the respective tissues. By far the most abundant ECM constituent in fibrotic tissues is collagen I, which is expressed and deposited at highly elevated levels and shows an abnormal macromolecular organization that leads to a disturbed tissue architecture, enhanced stiffness, contractures and tissue malfunction.In this project, we aim at modifying the excessive deposition of collagen by interfering with its secretion in fibroblasts, which are the main collagen producing cell type. Our previous work shows that TANGO1 activity is crucial for collagen secretion. We now want to use TANGO1 inhibitors to modulate excessive collagen deposition. Therefore, we aim to identify the molecular and cellular mechanisms following lack of and/or reduction of TANGO1 function and determine the cellular response. Specific peptide inhibitors will be generated and applied to fibroblasts from healthy individuals and patients with scleroderma as a model for fibrotic diseases to assess efficacy and molecular mechanisms of reducing collagen secretion. Application of the inhibitors to a murine model of skin fibrosis in vivo will complement our mechanistic in vitro studies and indicate, whether this approach might represent a promising therapeutic concept.

• DFG Programme: Research Grants
• International Connection: Spain
• Co-Investigator: Professorin Dr. Ines Neundorf
• Cooperation Partner: Professor Dr. Vivek Malhotra