PhD defence T. Luangmonkong
|When:||Mo 27-11-2017 09:00 - 11:00|
Exploring anti-fibrotic drugs
Focusing on an ex vivo model of fibrosis
Fibrosis is an integral part of the pathophysiological mechanism underlying numerous chronic diseases which account for up to 45% of deaths in the developed world. The fibrotic process is characterized by the excessive deposition of fibrous extracellular matrix in the affected organ, resulting in organ failure. Nevertheless, clinically effective anti-fibrotic drugs remain an unmet clinical need. In this thesis, Theerut Luangmonkong explored anti-fibrotic drugs for the treatment of liver fibrosis, and developed novel disease models, using precision-cut tissue slices.
The first part of Luangmonkong's thesis delineates the mechanism of liver fibrogenesis and the anti-fibrotic potency of several drugs affecting multiple pro-fibrogeneic mediators. He showed that galunisertib, a small molecule inhibitor against transforming growth factor beta, is an extremely promising drug candidate for the treatment of liver fibrosis; however, additional (clinical) studies are required to fully unveil its therapeutic potential. In addition, Luangmonkong demonstrated that several drugs affecting bone morphogenetic proteins, platelet-derived growth factor, p38-mitogen-activated protein kinase and reactive oxygen species also possess anti-fibrotic potency. Simultaneous inhibition of these pro-fibrogenic mediators might be clinically feasible and will greatly improve therapeutic efficacy.
Besides the successful use of precision-cut liver slices for drug discovery, Luangmonkong also used precision-cut tissue slices to develop experimental models of other multicellular diseases, namely non-alcoholic fatty liver disease and renal fibrosis. These newly established disease models will vastly support future research efforts into fibroproliferative diseases as well as drug development.