Role of PreS2 Mutants in Pathogenesis of Chronic Hepatitis B

描述(申请人提供)：乙肝病毒(乙肝病毒)是严重肝病的主要原因，包括慢性肝炎，肝硬变和肝细胞癌(肝细胞癌)在世界各地和美国，特别是在少数族裔包括非裔美国人，印第安人和亚裔美国人。然而，慢性乙型肝炎致癌的分子机制尚不清楚。其中一位主要研究人员和他的同事之前已经建立了一种新的乙肝病毒相关性肝癌的转基因小鼠模型，这是父母授予R01CA55578的主题。另一位首席研究员和他的同事最近证明了S亚硝化增加在自发性和致癌物诱导的肝细胞癌中的重要作用。具体地说，他们证明，缺乏S-亚硝基谷胱甘肽还原酶(GSNOR)的小鼠，无论是自发还是在致癌物治疗后患上肝癌的几率都比野生型小鼠高得多。此外，通过使小鼠也缺乏诱导型一氧化氮合酶(诱导型一氧化氮合酶)，可以消除肝细胞癌的发生，诱导型一氧化氮合酶是肝脏内S亚硝化的主要原因。由于文献中的数据表明诱导型一氧化氮合酶在乙肝中的表达升高，我们假设S亚硝化在乙肝病毒相关的肝细胞癌中同样起着关键作用。为了回应NOT-OD-09-058(“NIH宣布恢复法案资金可用于竞争性修订申请”)，我们提交这一竞争性修订，以便我们可以用两个特定的目标来检验我们的假设。1)我们将确定GSNOR缺陷是否会与乙肝病毒协同诱发肝细胞癌。2)我们将确定iNOS的消除是否会阻止GSNOR缺陷的HBV型转基因小鼠肝癌的发展。预计这些实验将为S-亚硝化在乙肝病毒相关性肝癌中的作用提供直接证据，并在未来导致识别肝癌风险最高的患者，并开发预防和/或治疗肝癌的有针对性的疗法。拟议的工作将通过雇佣更多的科学人员(2.5 FTE)以及购买用品、服务合同和旅行机票来刺激经济。 公共卫生相关性：乙肝病毒是世界上造成痛苦和死亡的主要原因，它会导致肝脏损伤、肝硬变(肝疤痕形成)和肝癌。它每年造成约100万人死亡。目前对乙肝的治疗既昂贵又不充分，而肝癌的治愈率极低。我们希望我们的研究能够导致开发新的方法来预防、检测和/或治疗这些患者的肝癌。

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.