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New York, New York 10006
AASLD/ALF Liver Scholar Award
USC Keck School of Medicine, Los Angeles, California
Identification of a novel host innate immune factor that regulates HCV
Current antiviral therapy against HCV consists of a combination of pegylated IFN-α (PEG-IFN)
and Ribavirin. However, Dr. Saito recognizes this treatment eradicates HCV in only 40-50% of patients following 48 weeks of treatment and has severe adverse effects. Therefore, improvement of IFN based therapeutic strategy is desperately needed for better therapeutic outcome and relief of medication-related toxicities.
IFN induces antiviral effects through the induction of approximately 200 interferon stimulated genes (ISGs). It is known that HCV proteins block induction and function of some of critical ISGs, leading us to hypothesize that those ISGs are critical to inhibit the HCV life cycle.
In this proposal, Dr. Saito has established a cell line stably expressing the interferon stimulated gene 56 (ISG56) promoter fused to a firefly luciferase reporter gene. Dr. Saito applied the cells to high throughput cDNA screening to identify novel antiviral host factors. The screening identified more than forty genes as potential candidates of antiviral gene inducers including tyrosine kinase, non-receptor, 1(TNK1). Preliminary experiments suggest that the TNK1 pathway promotes the expression of antiviral genes that suppress HCV replication. Moreover, virus infection and interferon (IFN) treatment each regulate TNK1 abundance, suggesting a regulatory feedback mechanism. These observations indicate that TNK1 is involved in the host response against virus infection and the antiviral action of IFN. In this proposal, Dr. Saito will focus on defining the mechanism of antiviral gene induction by TNK1 including investigation of the phosphorylation of candidate substrates of TNK1, determination of the signaling cascade of the TNK1 pathway, structure and function analysis of TNK1 to identify its signaling and substrate binding motifs. Furthermore, Dr. Saito will also assess how the antiviral activities of TNK1 control HCV in hepatocytes as a potential novel anti-HCV therapeutic target.
Finally, Dr. Saito will examine the effect of TNK1 combined with pegylated IFN-α (PEG-IFN) and Ribavirin or HCV NS3/4A protease inhibitor as a basis to investigate potential novel anti HCV treatments. Dr. Saito’s study stands to identify novel anti-HCV therapeutic strategies through the identification and characterization of TNK1 mediated antiviral signaling pathways.