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Role of hepatitis C virus (HCV) transactivating proteins in the pathogenesis of HCV-induced liver lesions and hepatocellular carcinoma (HCC)

Ziel

HCV infection affects more than 170 million people worldwide and is becoming the first cause of liver transplantation and primary liver cancer in industrialized countries. Whether HCV induces liver cancers through the cirrhosis it causes, or bears intrinsic carcinogenetic properties is debated, and the molecular mechanisms underlying HCV-related hepatocarcinogenesis remain unknown. The hosting laboratory (INSERM U635) has recently shown that quasispecies variants of HCV NS5A protein bear significantly different transactivating properties, according to their amino acid sequence. Such properties could play a role in the early steps of HCV-related hepatocarcinogenesis. We hypothesize that both the core and NS5A transactivating properties play a role in the triggering of early carcinogenetic events in HCV infection and that this role is modulated by the natural variability of these proteins. Intracellular production, even in low amounts, of proteins with strong transactivating properties could interact with cellular mechanisms and have transforming properties on hepatocytes, which may ultimately lead to HCC development.

In this project, we will: 1) characterize the natural genetic variability of core and NS5A variants and its functional impact on their transcription al activities in vitro; 2) study the consequences of HCV protein repertoire expression, ex vivo and in vivo, according to the transcriptional activity of core and NS5A protein variants, and 3) understand the role of transactivation properties carried by HCV proteins in the sequence of HCV-related liver pathogenesis. The originality of our project resides in two key fundamentals: 1) the use of HCV sequences directly cloned from chronically infected patients with well characterized hepatic consequences of HCV infection; and 2) the use of an original experimental animal model based on long-term expression of HCV proteins in the liver of mice transduced by helper-dependant adenoviral vectors.

Wissenschaftliches Gebiet (EuroSciVoc)

Schlüsselbegriffe

Thema/Themen

Aufforderung zur Vorschlagseinreichung

FP6-2004-MOBILITY-12
Andere Projekte für diesen Aufruf anzeigen

Finanzierungsplan

IRG - Marie Curie actions-International re-integration grants

Koordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MÉDICALE
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