Role of PreS2 Mutants in Pathogenesis of Chronic Hepatitis B

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DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a major cause of serious liver diseases, including chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) throughout the world and the US, especially among minorities including African Americans, Native Americans, and Asian Americans. Yet, the molecular mechanisms of carcinogenesis in chronic hepatitis B are unclear. One of the principal investigators and his colleagues has previously generated a novel transgenic mouse model of HBV-associated HCC, which is the subject of the parent grant R01CA55578. The other principal investigator and his colleagues recently demonstrated an important role for increased S-nitrosylation in spontaneous and carcinogen- induced HCC. Specifically, they demonstrated that mice deficient in S-nitrosoglutathione reductase (GSNOR), the major protein responsible for preventing the accumulation of S-nitrosylation, develop HCC both spontaneously and after carcinogen treatment at a much higher rate than wildtype mice. Furthermore, development of HCC can be eliminated by making the mice also deficient in inducible nitric oxide synthase (iNOS), the major cause of S-nitrosylation in the liver. Since data in the literature indicate that iNOS expression is elevated in hepatitis B, we hypothesize that S-nitrosylation similarly plays a critical role in HBV-associated HCC. In response to NOT-OD-09-058 ("NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications"), we are submitting this competitive revision so that we can test our hypothesis with two specific aims. 1) We will determine if GSNOR deficiency will synergize with HBV in inducing HCC. 2) We will determine if elimination of iNOS will block the development of HCC in the HBV-transgenic mice that are GSNOR deficient. It is anticipated that these experiments will provide direct evidence on the role of S-nitrosylation in HBV- associated HCC and lead in the future to the identification of patients most at risk for HCC and the development of targeted therapies for the prevention and/or therapy of HCC. The proposed work will stimulate the economy by enabling the hiring of additional scientific staff (2.5 FTE) and the purchase of supplies, service contracts, and travel tickets. PUBLIC HEALTH RELEVANCE: Hepatitis B virus is a major cause of suffering and death in the world, by causing liver injury, cirrhosis (liver scarring) and liver cancer. It causes approximately 1 million deaths annually. Current treatment for hepatitis B is expensive and inadequate, and liver cancer has an extremely low cure rate. We hope that our research can lead to the development of new ways to prevent, detect, and/or treat liver cancer in these patients.