Are connexin hemichannels and pannexin channels therapeutic drug targets and diagnostic biomarkers in cholestasis?

Connexin and pannexin proteins are the building stones of hemichannels and channels, respectively, which are transmembrane pores that mediate paracrine communication in numerous cell types. In healthy conditions, hepatocytes express connexin32, though in several liver pathologies, they switch to a connexin43-based mode, which is accompanied by increased pannexin1 production. Compelling evidence shows the involvement of connexin43 and pannexin1 (hemi)channels in inflammation and cell death, 2 typical features of cholestatic liver disease. Cholestatic liver pathologies are highly prevalent and constitute a major cause of drug-induced liver injury worldwide. This VUB-KUL joint project intends to investigate the potential of connexin43 and pannexin1 (hemi)channels as drug targets and biomarkers in cholestasis by relying on in vitro and in vivo models as well as on the testing of human cholestatic liver samples. As such, the objective is 2-fold, namely (i) to study the expression of connexin43 and pannexin1 in cholestasis, and (ii) to test the effects of connexin43 and pannexin1 (hemi)channel inhibition on cholestasis. Overall, this project, which combines fundamental with translational research, is considered of high clinical relevance, as it may introduce novel strategies for the treatment and diagnosis of cholestasis.