Karakterisatie van op connexine43- en pannexinel-gebaseerde hemikanalen als weefselbiomerkers en farmacologische doelwitten in acuut leverfalen: een gecombineerde in vitro-in vivo studie

Connexins and pannexins are the building stones hemichannels, which mediate extracellular communication. Hepatocytes typically express connexin32, though in several liver pathologies, including acute liver failure, they switch to a connexin43-based mode. Compelling evidence underscores a prominent function for connexin43-based hemichannel signalling in liver disease, in casu in acute liver failure, specifically in the process of cell death. On the other hand, pannexin1-based hemichannels were recently found to play a major role in the induction of liver inflammation. These features are the cornerstones of the current project. As such, the project has 3 goals. (i) The first goal is the elucidation of connexin43- and pannexin1-based signalling in cell death and inflammation in the context of acute liver failure. For this purpose, connexin43 and pannexin1 expression will be studied in liver tissue of an animal model of acute liver failure at the transcriptional, translational and activity levels. (ii) The second goal is the testing of novel connexin43 and pannexin1 mimetic peptides, developed as specific inhibitors of connexin43- and pannexin1-based hemichannels, in liver-derived in vitro models for their channel selectivity and their potential to suppress cell death and inflammation. (iii) As a part of the third goal, these compounds will be further scrutinized, whereby their in vivo outcome on pathology-specific read-outs in an established animal model of acute liver failure will be evaluated. Overall, this project, which combines fundamental with translational research, is considered of high clinical and pharmaceutical relevance, as it may introduce an innovative strategy for the treatment, and potentially also for the diagnosis, of acute liver failure.