Back to search form

Hepatitis C virus-induced alteration of miRNA networks and development of liver disease

Research unit

UMR_S 1110 - Intéraction virus-hôte et maladies hépatiques
3 rue Koeberlé, 67000 STRASBOURG

Group

Name: Interaction virus-hôte et maladies hépatiques

Group leader: BAUMERT Thomas - thomas.baumert@unistra.fr

Group leader's phone: 0368853703

Website: Visit website

Group organization:
- Chercheurs: 9
- ITA: 12
- Doctorants: 6
- Post-Docs: 9
- Autres: 2

Publications of the team linked to the topic (3 last years):
1) M.N. Zahid*, M. Turek*, F. Xiao, V.L. Dao Thi, M. Guérin, I. Fofana, P. Bachellier, J. Thompson, L. Delang, J. Neyts, D. Bankwitz, T. Pietschmann, M. Dreux, F-L. Cosset, F. Grunert, T.F. Baumert*, M.B. Zeisel*. The post-binding activity of scavenger receptor BI mediates initiation of hepatitis C virus infection and viral dissemination. Hepatology 2013; 57: 492-504
2) D. Da Costa*, M. Turek*, D. J. Felmlee*, E. Girardi, S. Pfeffer, G. Long, R. Bartenschlager, M. B. Zeisel*, T. F. Baumert*. Reconstitution of the entire hepatitis C virus life cycle in non-hepatic cells. Journal of Virology 2012; 86: 11919-25
3) J. Lupberger*, M.B. Zeisel*, F. Xiao, C. Thumann, I. Fofana, L. Zona, C. Davis, C.J. Mee, M. Turek, S. Gorke, C. Royer, B. Fischer, M.N. Zahid, D. Lavillette, J. Fresquet, F-L. Cosset, S.M. Rothenberg, T. Pietschmann, A.H. Patel, P. Pessaux, M. Doffoël, W. Raffelsberger, O. Poch, J.A. Mckeating, L. Brino, T.F. Baumert. EGFR and EphA2 are host factors for hepatitis C virus entry and potential targets for antiviral therapy. Nature Medicine, 2011; 17: 589-95

About PhD

PhD Director: ZEISEL Mirjam - mirjam.zeisel@unistra.fr

Phone: 0368853709

Junior advisor: non

Co-tutely: non

Co-Director: BAUMERT Thomas
University of Co-Director: Université de Strasbourg

About PhD topic :

Title: Hepatitis C virus-induced alteration of miRNA networks and development of liver disease

Project: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and hepatocellular carcinoma world-wide. Antiviral treatment is limited by resistance, high costs, and substantial side effects. A vaccine is not available. Noteworthy, successful antiviral treatment of HCV infection can revert steatosis and fibrosis and prevent advanced liver disease as well as HCC development. Elucidating the pathways implicated in the progression of HCV induced liver disease and HCC may therefore allow developing novel preventive and therapeutic concepts. Therefore, our laboratory aims at deciphering the molecular pathogenesis of HCV-induced liver disease to understand the sequence of events underlying pathogenesis of advanced liver disease and HCC. Well-characterized examples of pathways that are deregulated in cancer comprise protein kinases and micro(mi)RNAs, playing crucial roles in cell cycle, and thus tumor control. Recently, miR122, the most abundant liver miRNA, was identified as a tumor suppressor as miR122 knock-out mice develop liver cancer. While these data demonstrate that the absence of miR122 can lead to HCC in mice, analyses of human liver samples suggest that several miRNA pathways are deregulated in HCC patients. However, in spite of the dysregulation of several miRNAs in HCC, little is known about which miRNAs play critical roles in the pathogenesis of liver disease and their relevant targets remain to be determined.
To investigate whether HCV deregulates miRNA or noncoding (nc) RNA networks that are linked to liver disease, we have previously analyzed the miRNome in HCV-infected hepatoma cells in collaboration with Dr. Sébastien Pfeffer (UPR 9002, IBMC, Strasbourg). HCV infection markedly modulated the expression of a total of 122 out of 500 most abundant miRNAs expressed in Huh7.5 cells. HCV infection increased expression of three miRNAs that have been shown to be up-regulated in HCC and decreased three miRNAs that had been reported to be down-regulated in HCC. HCV infection most dramatically increased expression (10-fold) of one miRNA that had been reported to directly inhibit expression of the tumor suppressor gene RUNX3, which results in activation of Wnt/β-catenin signaling, a signaling pathway that has been linked to liver tumorigenesis.
The aim of this PhD project is to (i) validate the role of identified miRNAs in several model systems for HCV infection and to (ii) investigate the molecular mechanisms how the identified miRNAs affect HCV pathogenesis.
The first part of this PhD will consist in validating the miRNAs identified by expressing miRNAs and using antagomiRs and state-of-the-art model systems for HCV infection. Asssessing the moleculer mechanism of miRNA-virus-host interactions, the candidate will then determine whether the miRNAs directly interact with HCV RNA and/or whether these factors modulate the expression of host proteins. This will involve the use of bioinformatics and molecular virology and cell biology methods after the identification of seeds and target proteins. In the second part of the work, the candidate will investigate the molecular mechanisms underlying HCV pathogenesis and involving these host factors. Furthermore, miRNA networks will be revealed using bioinformatic analyses. This work will be conducted in close collaboration with Dr. S. Pfeffer (UPR 9002, IBMC, Strasbourg) a leading expert in the study of miRNA-virus-host cell interactions.
The identification of miRNA networks modulated upon HCV infection will allow to understand HCV pathogenesis and to develop new antiviral and vaccine approaches.

Wished skills: We would like to recruit a dynamic and highly motivated individual with interest in biomedical translational research and willing to integrate in an international scientific environment. The candidate should have technical experience in cell biology, biochemistry as well as cellular and molecular biology.

Expertises which will be acquired during the training: The candidate will be trained in molecular virology and cell biology including the following techniques: cloning of viral cDNA, site-directed mutagenesis, transfection, analysis of protein and RNA expression by immunoblot and Northern blot, flow cytometry, purification of virus, RNA and protein, study of viral replication using recombinant HCV, cell culture including BSL3 conditions, statistical analysis. Moreover, the candidate will have the opportunity to improve his English language skills and will be trained to give scientific presentations in English.