New mouse model of hepatitis B virus-associated hepatocellular carcinoma

乙型肝炎病毒相关肝细胞癌的新小鼠模型

• 批准号: 7302957
• 负责人: Tien-Sze Benedict Yen
• 金额: $ 23.64万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7302957
• 关键词: Abbreviations; African American; Alanine Transaminase; Animal Model; Asian Americans; Aspartate Transaminase; Biological Markers; Carcinogenesis Mechanism; Carcinogens; Cells; Cessation of life; Chronic; Chronic Hepatitis; Chronic Hepatitis B; Cicatrix; Cirrhosis; Clinical Data; Complication; DNA; Data; Development; Diagnosis; Disease; Endoplasmic Reticulum; Frequencies; Future; Genes; Genome; HIV; Hepatic; Hepatitis B Virus; Hepatocyte; Histopathology; Human; Human Virus; Inflammation; Initiator Codon; Injury; Lead; Lesion; Liver; Liver Cirrhosis; Liver diseases; Malignant neoplasm of liver; Measures; Membrane Proteins; Minority; Modeling; Molecular; Molecular Analysis; Mus; Mutation; Native Americans; Neoplasms; Nodule; Oncogenic; Open Reading Frames; Oxidative Stress; Patients; Play; Preventive; Primary carcinoma of the liver cells; Principal Investigator; Proteins; Research; Role; Specimen; Stress; Superoxide Dismutase; Surface; System; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Model; UCP2 protein; Viral; base; carcinogenesis; clinically relevant; cohort; design; insight; mouse model; mutant; neoplastic; novel; prevent; programs; promoter; protein expression; research study; response; virus pathogenesis

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.

描述（由申请人提供）：乙型肝炎病毒（HBV）是世界各地和美国，尤其是非洲裔美国人、亚裔美国人和美洲原住民等少数族裔中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）。然而，慢性乙型肝炎致癌的分子机制仍不清楚。尽管慢性炎症和饮食致癌物等非特异性因素显然发挥着重要作用，但尚无关于 HBV 特异性因素如何促进致癌的确切数据。最近的临床数据表明，HCC 和 HBV 突变体之间存在关联，其与表面基因 preS2 区域的框内缺失和/或错义起始密码子突变有关。更重要的是，我们已经培育出含有 preS2 突变型 HBV 基因组的转基因小鼠，并表明它们会发展为 HCC。因此，这些小鼠构成了 HBV 诱导的 HCC 的新型临床相关动物模型。我们提出两组实验。 1）我们将跟踪一组这些小鼠并研究它们在不同时间点的肝脏组织病理学，以便我们能够详细了解HCC形成的时间过程以及与前驱病变的关系。 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可能在机制上参与致癌作用。我们还将把小鼠数据与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，并为了解乙型肝炎病毒感染者致癌的分子基础奠定基础，从而为未来设计针对这种致命疾病的新型预防和治疗措施指明方向。乙型肝炎病毒是世界上造成痛苦和死亡的主要原因，它会导致肝损伤、肝硬化（肝脏疤痕）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，每年导致超过 120 万人死亡。目前的治疗方法昂贵且不足，我们相信我们的研究将导致开发预防、检测或治疗这些患者肝癌的新方法。