Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver diseases

• Grant number: 16/03579-8
• Support type: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): April 01, 2016
• Effective date (End): March 31, 2017
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal researcher: Mathieu Frederick Alexander Vinken
• Grantee: Valéria Veras Lopes
• Home Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/50420-6 - Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease, AP.SPEC

Abstract

Although being in its infancy and surrounded by controversy, it is now believed that connexin (Cx) hemichannels and pannexin (Panx) channels 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 intends to tackle this issue and to simultaneously verify the hypothesis that connexin hemichannels and pannexin channels may serve as drug targets and biomarkers in disease. Specific focus will be put on acute liver failure and liver fibrosis. As such, the CONNECT project has 3 scientific objectives, which are addressed in 3 corresponding workpackages (WP). The goal of the first WP is the characterization of Cx32, Cx43 and Panx1 expression in liver pathology. Both human diseased liver tissue and animal models of acute liver failure and liver fibrosis will be used for this purpose. Connexin and pannexin expression will be studied at the transcriptional and translational level, paralleled by probing of their channel activity. The goal of the second WP is the in vitro testing of inhibitors of connexin hemichannels consisting of Cx32 and Cx43, and Panx1 channels, namely Gap24, Gap19 and 10Panx1, respectively. Specific attention will be paid to their target selectivity and their potential to reduce cell death and inflammation in liver-based in vitro models. The goal of the third WP is the in vivo verification of the in vitro findings established in the second WP. This will be achieved by administering the channel inhibitors to animal models of acute liver failure or liver fibrosis and by subsequently evaluating their outcomes. Overall, the CONNECT project is anticipated to yield novel drug targets and biomarkers that can be used in the specific context of acute liver failure and liver fibrosis. The clinical impact and utility are, however, much larger, as its generic nature makes the findings of the CONNECT project transferrable to many other disease states and thereby may be of potential benefit to numerous patient groups worldwide. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

WILLEBRORDS, JOOST; MAES, MICHAEL; ALVES PEREIRA, ISABEL VELOSO; DA SILVA, TEREZA CRISTINA; GOVONI, VERONICA MOLLICA; LOPES, VALERIA VERAS; YANGUAS, SARA CRESPO; SHESTOPALOV, VALERY I.; NOGUEIRA, MARINA SAYURI; DE CASTRO, INAR ALVES; FARHOOD, ANWAR; MANNAERTS, INGE; VAN GRUNSVEN, LEO; AKAKPO, JEPHTE; LEBOFSKY, MARGITTA; JAESCHKE, HARTMUT; COGLIATI, BRUNO; VINKEN, MATHIEU. Protective effect of genetic deletion of pannexinl in experimental mouse models of acute and chronic liver disease. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1864, n. 3, p. 819-830, MAR 2018. Web of Science Citations: 5.