The Liver Research Center is a newly constructed 13,000-sq. ft. facility that will emphasize studies relating to the molecular biology of liver diseases. There are numerous ongoing studies that relate to the pathogenesis of hepatocellular carcinoma as well as a major effort in gene therapy of liver diseases. For example, we investigate the relationship of chronic hepatitis B and C infection and hepatocellular carcinoma at the molecular level. Of particular interest is the generation of naturally occurring viral variants that are produced during active viral replication or immune selection by the host. These mutations convey different biologic properties as compared to "wild type" virus. Such viral variants have different biologic properties including the development of viral latency, low level viral gene expression, increased virulence, vaccine escape and integration into the hepatocyte cellular DNA.

With respect to chronic hepatitis B infection, there are ongoing studies that examine the molecular mechanisms of viral integration into the cellular DNA during the development of cellular carcinoma with particular emphasis on hepatitis B viral variants. Attempts are being made to understand hepadnavirus hepatocyte cell surface receptor binding proteins. We are also interested in the functional role of the hepatitis Bx protein and these studies focus on the cloning and characterizing liver specific proteins that interact with HBx. Such investigations may have relevance to the hepatocyte transformation process since HBx in combination with cellular factors act as a transcriptional transactivator of many growth related genes.

Studies are ongoing on the development of antiviral approaches to interfere with HBV and HCV replication. These approaches include antisense oligonucleotides, ribozymes, dominant negative mutants and therapeutic viral DNA based vaccines. In this context, there is a major effort to develop vectors to specifically deliver DNA constructs to the liver and thus there is a major program in gene therapy of viral diseases of the liver. In this regard, we are using several approaches that include receptor mediated endocytosis of targeted liposomes and use of various adenovirus, retrovirus and adeno-associated virus constructs that express genes of interest in hepatocytes. Such approaches are also being applied to gene therapy of primary hepatocellular carcinoma using animal model systems.

Figure 1. Diagram depicting some of the major features of the insulin/IGF-1 signal transduction cascade involved in hepatocyte and human hepatocellular carcinoma cell growth.

There is also a major focus in the study of growth regulation of hepatocytes through growth factor receptors and intracellular signal transduction pathways with particular emphasis on the insulin stimulated hepatocyte growth. The expression and tyrosyl phosphorylation of insulin receptor substrate-1 (IRS-1) as well as activation of downstream MAP kinases are being studied in a variety of experimental systems as well as in human disease. Finally, the relationship of chronic HBV infection and activation of growth factor signal transduction cascade is being actively pursued at the molecular level.