Role of PreS2 Mutants in Pathogenesis of Chronic Hepatitis B

PreS2突变体在慢性乙型肝炎发病机制中的作用

• 批准号: 7812112
• 负责人: LIMIN LIU
• 金额: $ 84.03万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812112
• 关键词: African American; Age; Alkylation; Animal Model; Asian Americans; Cancerous; Carcinogenesis Mechanism; Carcinogens; Cessation of life; Chronic Hepatitis; Chronic Hepatitis B; Cicatrix; Cirrhosis; Complication; Contract Services; DNA Repair Enzymes; DNA lesion; Data; Development; Diagnosis; Environment; Funding; Future; Gene Mutation; Genes; Genetic; Glutathione Reductase; Hepatic; Hepatitis B; Hepatitis B Therapy; Hepatitis B Virus; Hepatocarcinogenesis; Hepatocyte; Human; Injection of therapeutic agent; Injury; Knock-out; Knowledge; Laboratory mice; Lead; Lesion; Literature; Liver; Liver Cirrhosis; Liver diseases; Malignant neoplasm of liver; Metabolism; Minority; Modeling; Molecular; Molecular Biology; Mouse Strains; Mus; Native Americans; Nitroso Compounds; O(6)-Methylguanine-DNA Methyltransferase; Oncogenic; Oxidoreductase; Pathogenesis; Pathway interactions; Patients; Play; Prevention strategy; Prevention therapy; Primary carcinoma of the liver cells; Principal Investigator; Proteins; Recovery; Research; Risk; Role; Study models; Testing; Transgenic Mice; Transgenic Model; Travel; United States National Institutes of Health; Virus Activation; Work; carcinogenesis; human NOS2A protein; insight; mouse S-nitrosoglutathione reductase; mouse model; multicatalytic endopeptidase complex; mutant; nitrosative stress; novel; novel strategies; overexpression; parent grant; prevent; promoter; public health relevance; repaired; research study; response; tumorigenesis

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.

描述（由申请人提供）：B肝炎病毒（HBV）是严重肝病的主要原因，包括全世界和美国的慢性肝炎、肝硬化和肝细胞癌（HCC），尤其是在少数民族中，包括非洲裔美国人、美洲原住民和亚裔美国人。然而，慢性B型肝炎癌变的分子机制尚不清楚。其中一位主要研究者和他的同事先前已经产生了一种新的HBV相关HCC转基因小鼠模型，这是R 01 CA 55578的主题。另一位主要研究者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，他们证明了S-亚硝基谷胱甘肽还原酶（GSNOR）缺陷的小鼠，负责防止S-亚硝基化积累的主要蛋白质，自发地和致癌物治疗后以比野生型小鼠高得多的速率发展HCC。此外，可以通过使小鼠也缺乏诱导型一氧化氮合酶（iNOS）来消除肝癌的发生，诱导型一氧化氮合酶是肝脏S-亚硝基化的主要原因。由于文献中的数据表明iNOS表达在B型肝炎中升高，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NOT-OD-09-058（“NIH宣布恢复法案资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测试我们的假设。1)我们将确定GSNOR缺乏是否会与HBV协同诱导HCC。2)我们将确定在GSNOR缺陷的HBV转基因小鼠中，iNOS的消除是否会阻断HCC的发展。预计这些实验将提供关于S-亚硝基化在HBV相关HCC中的作用的直接证据，并在未来导致识别最有HCC风险的患者和开发用于预防和/或治疗HCC的靶向疗法。拟议的工作将通过雇用额外的科学工作人员（2.5 FTE）和购买供应品、服务合同和旅行机票来刺激经济。 公共卫生相关性：B型肝炎病毒通过引起肝损伤、肝硬化（肝瘢痕形成）和肝癌而成为世界上痛苦和死亡的主要原因。它每年造成约100万人死亡。目前对B型肝炎的治疗既昂贵又不充分，肝癌的治愈率极低。我们希望我们的研究可以导致开发新的方法来预防，检测和/或治疗这些患者的肝癌。