New mouse model of hepatitis B virus-associated hepatocellular carcinoma

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），特别是在非洲裔美国人，亚裔美国人和印第安人等少数民族中。然而，慢性乙型肝炎致癌性的分子机制仍不清楚。虽然慢性炎症和饮食致癌物等非特异性因素发挥重要作用是显而易见的，但没有关于hbv特异性因素如何促进致癌的确凿数据。最近的临床数据指出HCC和HBV突变体与表面基因preS2区域的框架内缺失和/或错义启动密码子突变之间存在关联。更重要的是，我们培育了含有preS2突变HBV基因组的转基因小鼠，并证明它们会发展为HCC。因此，这些小鼠构成了一种新的和临床相关的hbv诱导的HCC动物模型。我们提出两组实验。1)我们将对这些小鼠进行队列研究，研究其肝脏在不同时间点的组织病理学，从而详细了解HCC形成的时间过程及其与前体病变的关系。2)我们将对这些肝组织进行分子分析，以确定内质网应激和氧化应激是否在机制上参与了癌变。我们还将把小鼠数据与我们将从人类肝脏标本中获得的数据联系起来。预计这些实验将验证这种独特的小鼠模型，并为了解hbv感染者致癌的分子基础提供基础，从而为设计这种致命疾病的新型预防和治疗措施指明未来的途径。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。它是仅次于人类免疫缺陷病毒的第二大致命人类病毒，每年导致120多万人死亡。目前的治疗是昂贵和不充分的，我们相信我们的研究将导致开发新的方法来预防、检测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 such as African Americans, Asian Americans, and Native Americans. Yet, the molecular mechanisms of carcinogenesis in chronic hepatitis B remain unsettled. Although it is clear that non-specific factors such as chronic inflammation and dietary carcinogens play important roles, there are no firm data on how HBV-specific factors may contribute to carcinogenesis. Recent clinical data have pointed to an association between HCC and HBV mutants with in-frame deletions and/or missense start codon mutation in the preS2 region of the surface gene. More importantly, we have generated transgenic mice containing a preS2 mutant HBV genome and shown that they develop HCC. These mice therefore constitute a novel and clinically relevant animal model of HBV-induced HCC. We propose two sets of experiments. 1) We will follow a cohort of these mice and study the histopathology of their livers at various time points, so that we can obtain a detailed understanding of the time course of HCC formation and the relationship to precursor lesions. 2) We will perform a molecular analysis of these liver tissues, to determine if ER stress and oxidative stress may be mechanistically involved in carcinogenesis. We will also relate the murine data to data we will obtain from human liver specimens. It is anticipated that these experiments will validate this unique mouse model and provide the groundwork for understanding the molecular basis of carcinogenesis in HBV-infected people, thereby pointing to future ways for designing novel preventive and therapeutic measures for this deadly disease. 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 is the second most deadly human virus, after human immunodeficiency virus, and causes more than 1.2 million deaths annually. Current treatment is expensive and inadequate, and we believe that our research will lead to the development of new ways to prevent, detect, or treat liver cancer in these patients.