Rapport final
Hemichannels as novel pharmacological targets and biomarkers of cholestasis - Vinken Mathieu
The current project was targeted towards the elucidation of the mechanisms that are involved in cholestatic liver injury, which is caused by the accumulation of noxious bile acids. Particular attention was paid to the role of cellular channels composed of connexin and pannexin proteins. These channels mediate extracellular communication and play critical roles in pathological processes, in particular in inflammation and cell death. A total of 4 studies has been performed, each that resulted in a research paper.
In a first study, the effects of genetic ablation of pannexin1 on cholestasis was investigated in vivo. It was found that cholestatic pannexin1 knock-out mice show increased inflammation, hepatocellular injury and anti-oxidant enzyme activity with a predominant immune response.
In a second study, in vitro and in vivo models of cholestatic liver injury were subjected to microarray analysis and showed major differences at the level of cell death and metabolism. Newly identified key events included endoplasmic reticulum stress, autophagy and necroptosis.
In a third study, the use of tools to predict cholestatic liver injury induced by drugs, in particular the cholestatic index and transcriptomic profiling, were tested for applicability to non-pharmaceutical chemicals. It was found that, although these tools are promising, further fit-for-purpose optimization is required.
In a fourth study, the effects of cholestasis on liver connexins were investigated in in vitro and in vivo models. While the outcome of cholestasis on connexin26 and connexin43 varied among the models, a more generalized repressing effect was seen for connexin32.