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CHRONIC HCV INFECTION INDUCES CELLULAR CIRCUITS DRIVING LIVER DISEASE AND HCC DEVELOPMENT

Mardi 5 novembre 2019 11:00 - Duree : 1 heure
Lieu : Salle de Conférence de l’IAB - Rond Point de La Chantourne, 38700 La Tronche (arrêt de tram Grand Sablon, ligne B)

Orateur : Joachim LUPBERGER (University of Strasbourg, France)

(HCC). It is currently believed that chronic HCV infection contribute to the development of liver disease indirectly via chronic inflammation and directly by virus-induced alternations of the hepatocyte homeostasis. Since HCV does not develop latency nor integrate into the host genome. Instead, in order to maintain and persist it has developed refined strategies to evade antiviral responses and to optimize conditions for its replication. Thereto, the virus is twisting essential aspects of host cell biology, i.e, signaling pathways, gene expression machinery, and metabolism. These chronic alternations have important consequences for the development of liver disease.

Using multiomics studies involving transcriptomics, proteomics, metabolomics and epigenetics combined with advanced bioinformatics our unit has developed a proteogenomic atlas recapitulating the molecular mechanisms of virus-host interactions and metabolic disease. This atlas combines infection models using hepatocyte-like cells with liver tissue specimens from HCV-infected chimeric mice and HCV-infected patients. Moreover, our unit identified an epigenetic footprint of chronic HCV infection that contribute to the elevated HCC risk in DAA cured patients.

Key findings demonstrate that HCV infection induces persistent EGFR signaling, which is a main driver of fibrogenesis and HCC in animal models. EGFR maintains STAT3 signaling and promotes viral evasion from IFN response. Moreover, our studies revealed that HCV induces STAT3, a key player during liver regeneration which is suppressing peroxisomal function in hepatocytes. This leads to an accumulation of very long-chain fatty acids in infected hepatocytes matching the clinical phenotype of HCV-induced steatosis in patients. Indeed, we demonstrated that impaired peroxisomal function associates with clinical outcomes and phenotypes in viral and metabolic liver disease. Importantly, key regulators of the identified pro-oncogenic signature and the metabolic pathways remain deregulated in DAA cured patients and chimeric mice.

Our unit is currently refining the role of the STAT3 regulatory network during liver disease development. We aim to identify potential targets for a future therapeutic intervention to restore the metabolic phenotype and to reverse disease progression in risk patients with and without HCV infection. Moreover, based on the identified epigenetic footprint of HCV infection we are currently developing biomarker to identify and stratify DAA-cured patients with elevated HCC risk.

Contact : karin.sadoul@univ-grenoble-alpes.fr

Discipline évènement : (Biologie / Chimie)
Entité organisatrice : (IAB)
Nature évènement : (Séminaire)
Evènement répétitif : (Mardis de l’IAB)
Site de l'évènement : Pôle Santé / La Tronche

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