| Development of new therapies for a variety of liver diseases in basic and clinical studies. 1. Viral hepatitis and hepatocellular carcinoma. Prevention of cirrhosis and hepatocellular carcinoma is achieved upon successful eradication of the virus. We will conduct phase-1 trials on HCV-protease inhibitors and HCV-RNA polymerase inhibitors. Dendritic cells from HCV patients are isolated and induced to express immuno-dominant HCV epitopes. These cells will be tested for their competence to induce HCV-selective T-lymphocyte responses and a program for therapeutic vaccination of HCV-infected patients will be developed. DC-based therapy may also be useful for the treatment of hepatocellular carcinoma. Viral hepatitis C is associated with steatosis of the liver and insulin resistance. Treatment of viral hepatitis has mainly been focused on anti-viral drugs. We hypothesize that the HCV-induced metabolic changes induce a state of partial drug resistance. In this theme we will study the mechanisms and the consequences of HCV-induced metabolic changes. Projects: 1a. Therapy of viral hepatitis: i - Antiviral drug trials; ii - Development of DC-based vaccination therapy for HCV and HCC; 1b. Metabolic consequences of viral hepatitis. 2. Bile acid and lipid metabolism. Bile acids have recently been established as powerful signaling molecules that directly interact with a number of transcription factors, particularly FXR. FXR represses SREBP1c a transcription factor that controls the lipogenesis in the liver. In the intestine FXR activates genes involved in the innate immune response. Drugs that act as FXR agonists may be of interest in the treatment of a variety of diseases including non-alcoholic steatohepatitis, spontaneous bacterial peritonitis, primary sclerosing cholangitis. Projects: 2a. Non-alcoholic steatohepatitis; 2b. Bile acids as metabolic signals. 3. Liver support systems and hepatocyte transplantation. Currently liver transplantation is the main therapy of patients with acute and chronic liver failure. Successful application of liver support systems may replace liver transplantation to some extent. The bio-artificial liver may be applied to patients with acute liver failure, either as a bridge to liver transplantation, or to avoid transplantation if the liver is able to regenerate after severe injury. There is an increasing interest in human hepatocyte transplantation. From this experience it is clear that the therapeutic window for human hepatocyte transplantation has to be carefully explored before this technique can be successfully applied. Projects: 3a. Bio-artificial liver; 3b. Human hepatocyte transplantation. 4. Endothelin-receptor antagonists in portal hypertension. Endothelin receptor expression is upregulated in portal hypertension. Portal hypertension may in part be the consequence of an exaggerated response to endothelin. Endothelin receptor antagonists may become important drugs for the treatment of portal hypertension, hepatorenal syndrome, portopulmonary hypertension and variceal hemorrhage. Project: Efficacy and toxicity of endothelin receptor antagonists in patients with portal hypertension. |
