Role of PreS2 Mutants in Pathogenesis of Chronic Hepatitis B

描述（由申请人提供）：乙型肝炎病毒（HBV）是全球和美国严重肝脏疾病的主要原因，包括慢性肝炎，肝硬化和肝细胞癌（HCC），特别是少数民族，包括非洲裔美国人，美洲原住民和亚裔美国人。然而，慢性乙型肝炎致癌性的分子机制尚不清楚。其中一名主要研究人员和他的同事先前已经建立了一种新的hbv相关HCC转基因小鼠模型，这是父母资助R01CA55578的主题。另一位首席研究员和他的同事最近证明了s -亚硝基化增加在自发性和致癌物诱导的HCC中的重要作用。具体来说，他们证明缺乏s -亚硝基谷胱甘肽还原酶（GSNOR）的小鼠自发发生HCC，并在致癌物治疗后比野生型小鼠高得多。GSNOR是负责防止s -亚硝基化积累的主要蛋白质。此外，可以通过使小鼠也缺乏诱导型一氧化氮合酶（iNOS）来消除HCC的发展，iNOS是肝脏中s -亚硝基化的主要原因。由于文献数据表明乙型肝炎中iNOS表达升高，我们假设s -亚硝基化在hbv相关的HCC中同样起着关键作用。作为对no - od -09-058（“NIH宣布恢复法案基金可用于竞争性修订申请”）的回应，我们提交了这一竞争性修订，以便我们可以用两个具体目标来检验我们的假设。1)我们将确定GSNOR缺乏是否会与HBV协同诱导HCC。2)我们将确定消除iNOS是否会阻断GSNOR缺陷的hbv转基因小鼠的HCC发展。预计这些实验将为s -亚硝基化在HBV相关HCC中的作用提供直接证据，并在未来导致HCC最危险患者的识别和肝癌预防和/或治疗的靶向治疗的发展。拟议的工作将通过雇用额外的科学人员（2.5 FTE）和购买用品、服务合同和旅行机票来刺激经济。

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.