application) Hepatitis C virus (HCV) infection and its complications are emerging as an extraordinarily important public health problem worldwide. Hepatocellular carcinoma (HCC) is now a firmly established and largely incurable complication of chronic HCV, and its prevalence in this country will continue to grow as a large cohort of patients infected decades ago comes to clinical attention. While most cases appear to arise in the setting of chronic inflammation, cirrhosis, and regeneration, the pathogenesis of HCV-related HCC remains unknown. It becomes apparent that a fundamental understanding of the mechanisms of HCV-related hepatocarcinogenesis is essential to effectively address this major sequel to chronic infection. Animal models of HCV-related hepatocarcinogenesis have been difficult to construct, in great part because of the obstacles to creation of a model permissive for infection. Transgenic mouse models permit the opportunity to examine the effects of selective expression of viral proteins. A recent report has suggested that transgenic mice expressing the HCV core protein alone develop HCC. We have created a transgenic mouse model that successfully expresses HCV core as well as the two envelope glycoproteins; however, these animals do not develop liver disease. The basis for these observed differences is unknown. We propose to explore the contributions of three major arms -to HCV-related HCC: (1) viral protein expression; (2) host genetic predisposition; and (3) the host immune response. To accomplish this, we will use novel transgenic mouse models to explore the direct contribution of both HCV structural to explore the mechanistic differences between our model and the core model. We will also cross our transgenic HCV structural protein mice with a recently developed mutant tumor suppressor gene mouse model that spontaneously develops HCC in a large portion of aging animals. This cross will allow us to """"""""read out"""""""" the contribution of viral protein expression to HCC development (by increased frequency or acceleration of HCC formation), as well as to determine whether HCV-induced HCC requires a host genetic predisposition- Finally, we will create a novel, inducible transgenic model that expresses the full length HCV polyprotein to explore the contribution of activation of the host immune system to HCV-related hepatocarcinogenesis. Together, these models will help provide insights into the factors responsible for this devastating complication of chronic HCV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK057857-01
Application #
2907719
Study Section
Special Emphasis Panel (ZDK1-GRB-5 (M1))
Program Officer
Doo, Edward
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
1999-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Delgado-Borrego, Aymin; Liu, Yun-Sheen; Jordan, Sergio H et al. (2008) Prospective study of liver transplant recipients with HCV infection: evidence for a causal relationship between HCV and insulin resistance. Liver Transpl 14:193-201
Tokumoto, Yoshio; Hiasa, Yoichi; Horiike, Norio et al. (2007) Hepatitis C virus expression and interferon antiviral action is dependent on PKR expression. J Med Virol 79:1120-7
Hiasa, Yoichi; Blackard, Jason T; Lin, Wenyu et al. (2006) Cell-based models of sustained, interferon-sensitive hepatitis C virus genotype 1 replication. J Virol Methods 132:195-203
Kamegaya, Yoshitaka; Hiasa, Yoichi; Zukerberg, Lawrence et al. (2005) Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis. Hepatology 41:660-7
Lin, Wenyu; Choe, Won Hyeok; Hiasa, Yoichi et al. (2005) Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology 128:1034-41
Chung, Raymond T (2005) Acute hepatitis C virus infection. Clin Infect Dis 41 Suppl 1:S14-7
Leung, Jessica Y; Zhu, Andrew X; Gordon, Fredric D et al. (2004) Liver transplantation outcomes for early-stage hepatocellular carcinoma: results of a multicenter study. Liver Transpl 10:1343-54
Delgado-Borrego, Aymin; Casson, Deborah; Schoenfeld, David et al. (2004) Hepatitis C virus is independently associated with increased insulin resistance after liver transplantation. Transplantation 77:703-10
Hiasa, Yoichi; Kamegaya, Yoshitaka; Nuriya, Hideko et al. (2003) Protein kinase R is increased and is functional in hepatitis C virus-related hepatocellular carcinoma. Am J Gastroenterol 98:2528-34

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