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American Liver Foundation
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New York, New York 10006
American Liver Foundation Postdoctoral Research Fellowship Award
Stanford University, Stanford, California
“Investigating a protective role for miR-122 in the life cycle of Hepatitis C virus”
Hepatitis C virus (HCV) infection is a rapidly increasing global health problem with over 170 million people infected worldwide. HCV is a hepatotropic, positive-sense RNA virus of the family Flaviviridae. MicroRNA-122 (miR-122) is a highly abundant, liver-specific human microRNA that interacts with two sites in the 5’ end of the HCV RNA genome. Sequestration of miR-122 leads to a loss of viral RNA in cell culture and in vivo. Curiously, miR-122 does not affect viral translation and has a minimal affect on the rate of RNA synthesis. Dr. Sagan has recently demonstrated that miR-122 binds to the 5’ terminus of the HCV genome, suggesting that miR-122 may protect the terminus of the HCV RNA from attack by nucleases or cellular sensors of RNA. In this study she will investigate the character of the 5’ terminus of the viral genome during infections. Dr. Sagan will also directly investigate specific gene candidates for their role in HCV RNA recognition and turnover by carrying out short-interfering RNA (siRNA) knockdown during miR-122 sequestration of specific nucleases and cellular sensors of RNA. Finally, a genome-wide siRNA screen will identify genes mediating HCV RNA accumulation during miR-122 sequestration. The proposed research is highly significant as it examines the mechanism by which miR-122 modulates HCV RNA abundance and will help to identify novel host-virus interactions, defining new targets for therapeutic intervention.