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。特别是，在文献中没有令人信服的证据表明HBV本身是致癌的。最近的临床数据表明，HCC和HBV突变体与表面基因preS2区域的框架内缺失有关，这种缺失会导致内质网应激。我们已经产生了含有preS2突变HBV基因组的转基因小鼠，并发现这些小鼠发展为HCC。这是第一次使用具有临床相关性的HBV全基因组转基因小鼠模型直接证明HBV诱导的致癌作用，因此这些小鼠代表了与人类HBV相关的HCC直接相关的唯一模型。我们假设preS2突变HBV基因组通过诱导内质网应激、氧化应激、线粒体损伤和核DMA损伤，在人类HBV相关癌变中发挥重要作用。我们将用三个具体目标来检验这一假设。1)我们将从基因组不稳定性、基因位点扩增或缺失、β -连环蛋白突变等方面对这些转基因小鼠的肿瘤进行表征，并将结果与已发表的HBV引起的人类HCC数据进行比较。2)我们将确定是否可以在我们的转基因小鼠和感染preS2突变体的人肝脏中检测到氧化应激、线粒体损伤和核DMA损伤；3)我们将确定用抗氧化剂治疗这些小鼠是否会降低HCC的发生率。预计这些实验将为preS2突变体在HCC形成中的作用提供直接证据，开始阐明HBV感染期间致癌的分子机制，并在未来确定预防和/或治疗HCC的分子靶点。乙型肝炎病毒是世界上造成痛苦和死亡的一个主要原因，它会导致肝损伤、肝硬化（肝瘢痕）和肝癌。它每年造成120多万人死亡。目前对乙肝的治疗既昂贵又不充分，而肝癌治愈率极低。我们希望我们的研究可以引导新的方法来预防、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. In particular, it has not been convincingly shown in the literature that HBV itself is carcinogenic. Recent clinical data have pointed to an association between HCC and HBV mutants with in-frame deletions in the preS2 region of the surface gene that cause stress in the endoplasmic reticulum. We have generated transgenic mice containing a preS2 mutant HBV genome, and found that these mice develop HCC. This is the first direct demonstration of carcinogenesis induced by HBV in a transgenic mouse model using the entire HBV genome that is clinically relevant, and thus these mice represent the only model that is directly relevant to human HBV-associated HCC. We hypothesize that preS2 mutant HBV genomes play an important role in human HBV-associated carcinogenesis, by inducing stress in the endoplasmic reticulum, followed by oxidative stress, mitochondrial damage, and nuclear DMA damage. We will test this hypothesis with three specific aims. 1) We will characterize the neoplasms in these transgenic mice in terms of genomic instability, genetic loci with amplifications or deletions, and beta-catenin mutations, and compare the results with published data on human HCC caused by HBV. 2) We will determine if oxidative stress, mitochondrial damage, and nuclear DMA damage can be detected in our transgenic mice and in human livers infected with preS2 mutants; 3) We will determine if treatment of these mice with antioxidants will reduce the incidence of HCC. It is anticipated that these experiments will provide direct evidence on the role of preS2 mutants in HCC formation, begin to elucidate the molecular mechanisms of carcinogenesis during HBV infection, and lead in the future to the identification of molecular targets for the prevention and/or therapy of HCC. 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 more than 1.2 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.