Genetic and epigenetic regulation of Hepatitis B contributes to liver cancer

乙型肝炎的遗传和表观遗传调控导致肝癌

• 批准号: 7551997
• 负责人: MICHAEL S TORBENSON
• 金额: $ 34.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7551997
• 关键词: Address; Animal Model; Biological; Biological Models; Categories; Cells; Chronic Hepatitis B; Cirrhosis; Control Groups; CpG Islands; DNA Modification Methylases; Data; Development; Elements; Enzymes; Epigenetic Process; Etiology; Frequencies; Gene Expression; Genetic; Goals; Hepatic; Hepatitis; Hepatitis B; Hepatitis B Therapy; Hepatitis B Vaccines; Hepatitis C; Hepatocyte; High Prevalence; Human; Human Genome; Immune system; Lead; Liver; Liver diseases; Malignant neoplasm of liver; Methylation; Methyltransferase; Modeling; Modification; Morbidity - disease rate; Mutation; Nucleic Acids; Phenotype; Predictive Value; Prevalence; Prevention; Primary carcinoma of the liver cells; Production; Protein Family; Proteins; Publishing; Regulation; Risk; Sampling Studies; Serum; Staging; Testing; Therapeutic; Tissue Sample; Tissues; Tumor Suppressor Genes; Viral; Viral Genes; Viral Genome; Viral hepatitis; Virus Diseases; carcinogenesis; effective therapy; established cell line; human disease; human tissue; intrahepatic; mortality; novel; prevent; promoter; therapeutic target; viral DNA; viral RNA

DESCRIPTION (provided by applicant): This proposal studies how certain elements of the innate immune system regulate levels of hepatitis B viral (HBV) DNA in liver tissues through genetic and epigenetic modification of viral DNA and how these same elements of the innate immune system contribute to carcinogenesis. This proposal is directly relevant to expanding our understanding of how chronic HBV infection leads to hepatocellular carcinoma. Recent advances in the understanding of HBV infection have shown that the risk for developing HCC is directly proportional to the serum levels of HBV DNA and reducing serum levels of HBV DNA are a major therapeutic target in the treatment of HBV. The biological mechanisms by which the host controls intrahepatic HBV replication remain incompletely understood, but better understanding may lead to more effective treatments that will prevent the development of HCC. We hypothesize that intrahepatic HBV levels are partly regulated by portions of the innate immune system that lead to mutations in the HBV genome through activation of the APOBEC family of proteins and that host methyltransferases methylate the HBV genome, leading to decreased HBV gene expression. We further hypothesize that these mechanisms contribute to carcinogenesis by leading to increased methylation of tumor suppressor genes (corresponding to the methylator phenotype in hepatocellular carcinoma). In Aim One, we will determine the frequency of APOBEC induced hypermutations of the HBV genome in livers with chronic HBV infection and test the hypothesis that the extent of hypermutations predictes levels of HBV DNA. In Aim Two, we will determine the frequency of methylation and the quantitative levels of methylation of non-integrated HBV using qualitative and quantitative methylation specific PCR and test the hypothesis that methylation levels of HBV DNA is predicitive of the levels of intrahepatic HBV. We also test the hypothesis that human cells can directly methylate HBV DNA and investigate the methyltransferases responsible. In Aim Three, we study HBV associated HCCs to explore the hypothesis that they will demonstrate increased levels of tumor suppressor gene methylation. These studies will significantly advance our understanding and potentially our ability to treat HCC. This proposal studies how certain elements of the innate immune system regulate levels of hepatitis B viral (HBV) DNA in liver tissues through genetic and epigenetic modification of viral DNA and how these same elements of the innate immune system contribute to carcinogenesis.

描述（由申请人提供）：本提案研究先天免疫系统的某些要素如何通过病毒 DNA 的遗传和表观遗传修饰来调节肝组织中乙型肝炎病毒 (HBV) DNA 的水平，以及先天免疫系统的这些相同要素如何促进致癌。该提议与扩大我们对慢性乙型肝炎病毒感染如何导致肝细胞癌的理解直接相关。对 HBV 感染认识的最新进展表明，发生 HCC 的风险与血清 HBV DNA 水平成正比，降低血清 HBV DNA 水平是治疗 HBV 的主要治疗目标。宿主控制肝内 HBV 复制的生物学机制仍不完全清楚，但更好的理解可能会带来更有效的治疗，从而预防 HCC 的发展。我们假设肝内 HBV 水平部分受到先天免疫系统部分的调节，这些部分通过激活 APOBEC 蛋白家族导致 HBV 基因组突变，并且宿主甲基转移酶使 HBV 基因组甲基化，从而导致 HBV 基因表达降低。我们进一步假设这些机制通过导致肿瘤抑制基因甲基化增加（对应于肝细胞癌中的甲基化表型）而促进癌发生。在目标一中，我们将确定慢性 HBV 感染肝脏中 APOBEC 诱导的 HBV 基因组超突变的频率，并检验超突变程度预测 HBV DNA 水平的假设。在目标二中，我们将使用定性和定量甲基化特异性 PCR 确定非整合 HBV 的甲基化频率和甲基化定量水平，并检验 HBV DNA 甲基化水平可预测肝内 HBV 水平的假设。我们还测试了人类细胞可以直接甲基化 HBV DNA 的假设，并研究了相关的甲基转移酶。在目标三中，我们研究了 HBV 相关的 HCC，以探索其肿瘤抑制基因甲基化水平升高的假设。这些研究将显着增进我们对 HCC 的理解，并有可能提高我们治疗 HCC 的能力。该提案研究先天免疫系统的某些要素如何通过病毒 DNA 的遗传和表观遗传修饰来调节肝组织中乙型肝炎病毒 (HBV) DNA 的水平，以及先天免疫系统的这些相同要素如何促进致癌。