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The CONNECT team

The CONNECT team (connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease) is part of the Department of Toxicology of the Faculty of Medicine and Pharmacy at the Vrije Universiteit Brussel (VUB)-Belgium and the Department of Pathology of the School of Veterinary Medicine and Animal Science of the University of São Paulo (USP)-Brazil.

RELEVANT PUBLICATIONS

Our relevant publications

RESEARCH CONTEXT

Tissue homeostasis is controlled by a plethora of communication mechanisms. At the intercellular level, gap junctions allow the trafficking of small and hydrophilic messengers between adjacent cells. Gap junctions are built up by 2 connexin hemichannels, which in turn are built up by 6 connexin (Cx) proteins. Today, 21 different connexin family members have been identified, all which are expressed in a cell-specific way and that are named according to their molecular weight. In liver, hepatocytes mainly produce Cx32 next to small quantities of Cx26, while non-parenchymal hepatic cells predominantly harbor Cx43. Gap junctional intercellular communication plays a key role in virtually all aspects of the cellular life cycle. In this respect, gap junctions in liver are known to underlie proliferation and cell death as well as several liver-specific functions, such as the biotransformation of drugs, glycogenolysis, albumin secretion and ammonia synthesis. However, in the last decade, it has become clear that the picture is not as straightforward as initially anticipated. Indeed, substantial evidence now shows that connexin hemichannels are much more than only being structural precursors of gap junctions, as they also may provide a pathway for communication, albeit between the cytosol of individual cells and their extracellular environment. In addition, a novel class of connexin-like proteins has been identified, the so-called pannexins, which gather in a configuration reminiscent of connexin hemichannels and that also facilitate extracellular signaling. Similar to connexins, pannexins are expressed in a cell-specific way, with Panx1 being produced by hepatocytes and selected non-parenchymal liver cells. Although a number of physiological functions have been attributed to both connexin hemichannels and pannexin channels, they have yet been mainly studied in a pathological context. In this regard, while Cx32 and Cx43 hemichannels dictate liver cell death, Panx1 is a critical determinant of inflammatory processes in hepatic tissue. These deleterious processes are frequently associated with drastic changes in the production of the channel building stones. In case of liver disease and toxicity, Cx32 expression gradually declines and becomes replaced by Cx43.

 Figure: A. Architecture of connexin-based and pannexin-based channels. Gap junctions are formed by the interaction between 2 connexin hemichannels of adjacent cells and mediate intercellular communication (red arrow). Connexin hemichannels and pannexin channels are built up by 6 connexin proteins (green) and 6 pannexin proteins (blue), respectively, and support paracrine communication (purple). B. Topology of connexin and pannexin proteins. Connexins (green) and pannexins (blue) all consist of 4 transmembrane domains (TM), 2 extracellular loops (EL), 1 cytosolic loop (CL), 1 cytosolic carboxyterminal tail (CT) and 1 cytosolic aminoterminal tail (NT).

RESEARCH MISSION

The CONNECT team explores connexin and pannexin signaling in the context of liver pathology and has 2 main objectives:

1. To test connexin hemichannels and pannexin channels as drug targets for the clinical therapy of liver disease.

2. To test connexin and pannexin proteins as biomarkers for the clinical diagnosis of liver disease.

Focus is hereby put on both acute and chronic liver diseases, including drug-induced liver failure, non-alcoholic fatty liver disease/steatohepatitis, liver fibrosis and cholestasis. Throughout this research, specific attention is paid to the development of novel chemical tools that allow specific inhibition of connexin hemichannels or pannexin channels in vivo and that can be used for detecting their building blocks in hepatic tissue and serum. The CONNECT research relies on mechanistic in vitro experimentation, the use of human-relevant mouse models of liver disease and the testing of human clinical samples. This combination of fundamental and translational research is unique and is increasingly gaining international interest from both clinicians and (bio)pharmaceutical companies.

At Vrije Universiteit Brussel-Belgium

  

 

  • Prof. Dr. Pharm. Mathieu Vinken
  • Drs. Lic. Sara Crespo Yanguas
  • Drs. Pharm. Eva Gijbels
  • Drs. Pharm. Axelle Cooreman
  • Drs. Pharm. Raf Van Campenhout
  • Miss Tineke Vanhalewyn
  • Miss Dinja De Win

At University of São Paulo-Brazil

  • Prof. Dr. D.V.M. Bruno Cogliati
  • Dr. Lic. Tereza Cristina da Silva
  • Dr. Lic. Isabel Veloso Alves Pereira
  • Drs. Lic. Cintia Maria Monteiro de Araújo
  • Drs. Lic. Tayna Tiburcio

Research communities and alliance groups

1. “VUB-UGent alliance research group “Connexin signaling research group”

Vrije Universiteit Brussel-Universiteit Gent: 01/01/2011-31/12/2020.

2. “VUB-USP alliance research group “Liver connexin and pannexin research group”

Vrije Universiteit Brussel-University of São Paulo: 01/01/2014-31/12/2020. 

3. “FWO research community “Connexin and pannexin channels: regulation, functions and applications”

Fund for Scientific Research Flanders: 01/01/2010-31/12/2020.

Contact

Prof. Mathieu Vinken
CONNECT team
Department of Toxicology
Faculty of Medicine and Pharmacy

Vrije Universiteit Brussel
Laarbeeklaan 103
1090 Brussels
Belgium

Telephone: +32-2-4774587
Fax: +32-2-4774582
E-mail: mvinken@vub.ac.be

Publications