Role of PreS2 Mutants in Pathogenesis of Chronic Hepatitis B

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。特别是，在文献中没有令人信服地表明HBV本身是致癌的。最近的临床数据指出，HCC和HBV突变体之间存在关联，这些突变体在表面基因的preS 2区域具有框内缺失，导致内质网应激。我们已经产生了含有前S2突变HBV基因组的转基因小鼠，并发现这些小鼠发生HCC。这是第一次直接证明HBV在转基因小鼠模型中诱导的致癌作用，该模型使用了临床相关的整个HBV基因组，因此这些小鼠代表了与人HBV相关HCC直接相关的唯一模型。我们推测，前S2突变的HBV基因组在人类HBV相关的致癌作用中起着重要作用，通过诱导内质网应激，随后是氧化应激，线粒体损伤和核DMA损伤。我们将以三个具体目标来检验这一假设。1)我们将根据基因组不稳定性、基因位点扩增或缺失以及β-连环蛋白突变来表征这些转基因小鼠中的肿瘤，并将结果与已发表的HBV引起的人类HCC的数据进行比较。2)我们将确定在我们的转基因小鼠和感染preS 2突变体的人类肝脏中是否可以检测到氧化应激，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的发病率。预计这些实验将提供直接的证据前S2突变体在HCC形成中的作用，开始阐明HBV感染过程中致癌的分子机制，并导致在未来识别的分子靶点，用于预防和/或治疗HCC。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120多万人死亡。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。

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.