The long term objective of this program is to elucidate the pathogenesis of hepatocehular carcinoma in hepatitis B virus (HBV) infection. In order to create the opportunity and the reagents to pursue these questions, we have introduced subgenolic fragments or the complete HBV genome into the germline of transgenic mice. In the course of these studies we developid a model of hepatocellular carcinoma in those lineages of transgenic mice that overexpress the HBV large envelope (preS1) polypeptide in their hepatocytes. These mice produce long subviral envelope filamentous particles which accumulate within the endoplasmic reticulum, leading to the formation of ground glass hepatocytes identical to those found in chronic HBV infection in man. For unknown reasons, these ground glass cells die and, thereby, elicit hepatocellular regeneration and a secondary inflammatory response with the eventual development of HCC. We now wish to characterize this model further, with the following Specific Aims: Speciric Aim 1. To clarify the relationship between the ground glass hepatocyte, liver cell injury and hepatocellular carcinoma in this model. Speciric Aim 2. To examine the role of oxidative damage in hepatocarcinogenesis, and the ability of antioxidants to prevent hepatocellular carcinoma in this model.
Specific Aim 3. To identify cellular genes whose expression is specifically altered during evolution of HCC that might be used to construct a tumor speciric vaccine in this model.
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