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.
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