Platelets as initiators and mediators of liver fibrosis

• Applicant: Dr. Hacer Sahin
• Subject Area: Gastroenterology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258301622

Liver fibrosis is the outcome of nearly all chronic liver diseases and represents a massive health care burden worldwide. Recently, we could show that platelets and their mediators are intrinsically involved in liver fibrosis. In this process, the hepatic infiltration and adhesion of platelets are functionally linked to recruitment of leukocytes. However, the molecular mediators and structures which facilitate these interactions remain elusive.The surface molecule Junctional Adhesion Molecule-A (JAM-A) is known to be involved in adhesion and recruitment of platelets and leukocytes into peripheral tissues.Crucially, our preliminary data show that the loss of platelet adhesion by platelet specific deficiency ameliorates experimental liver fibrosis and hepatic leukocyte recruitment in mice.Here, we hypothesize that JAM-A mediates the adhesion of platelets, thus triggering leukocytes into the liver which in turn perpetuate liver injury and fibrogenic processes. This hypothesis should be proven by 4 specific objectives.To this end, PF4 Cre mice were crossed to mice expressing the floxed JAM-A gene to generate a platelet specific knockout. This, combined with in vitro experiments, will help to elucidate the functional role of JAM-A in liver fibrosis and may provide the basis for an potential therapy with neutralizing antibodies to JAM-A.

• DFG Programme: Research Grants
• International Connection: Netherlands
• Participating Persons: Professor Rory R. Koenen, Ph.D.; Professor Frank Tacke, Ph.D.; Professor Dr. Marc van Zandvoort