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CONNECT Report Summary

Project ID: 335476
Funded under: FP7-IDEAS-ERC
Country: Belgium

Mid-Term Report Summary - CONNECT (Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease)

Evidence is accumulating indicating that connexin and pannexin hemichannels can act as pathological pores that connect the cytoplasm of cells with the extracellular environment and which facilitate cell death and inflammation. This is considered of high clinical relevance, as it offers the possibility to therapeutically limit the propagation of both processes and thus the manifestation of a plethora of diseases. The CONNECT project specifically addresses liver disease in this respect and has 2 main objectives, namely (i) to test connexin and pannexin hemichannels as drug targets for the clinical treatment of acute liver failure and liver fibrosis, and (ii) to test connexin and pannexin proteins as biomarkers for the clinical diagnosis of acute liver failure and liver fibrosis. In the first part of the CONNECT project, focus has been put on the acute liver failure aspect, in particular acute liver toxicity induced by the analgesic acetaminophen. Following the establishment of a human-relevant mouse model of acetaminophen-induced acute liver failure, connexin43 production was shown to increase in liver tissue at the expense of connexin26 and, especially, connexin32. This is due, at least in part, to de novo production by hepatocytes, being the main liver cell population. Using mice genetically deficient in connexin43, it was found that connexin43 protects against acetaminophen-induced acute liver failure. Furthermore, pharmacological suppression of pannexin1 hemichannel activity was demonstrated to alleviate liver toxicity induced by acetaminophen based on a series of clinically and mechanistically relevant parameters. Preliminary conclusions from the ongoing CONNECT project thus are (i) acute liver failure is associated with increased connexin43 expression in liver tissue, suggesting a role as a diagnostic biomarker, and (ii) pharmacological inhibition of pannexin1 hemichannels reduces the clinical manifestation of acute liver failure, suggesting a role as a therapeutic drug target. These findings will be scrutinized in the second part of the CONNECT project and will run in parallel with the studies on liver fibrosis as prototypical chronic liver disease.

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