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

基本信息

批准号：
8007383
负责人：
MICHAEL S TORBENSON
金额：
$ 34.16万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-15 至 2012-11-30
项目状态：
已结题

项目摘要

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）：该提案研究了先天免疫系统的某些元素如何通过遗传和表观遗传学的改性病毒DNA调节肝组织中丙型肝炎病毒（HBV）DNA水平，以及如何对先天免疫系统的这些相同元素有助于癌变。该提案与扩展我们对慢性HBV感染如何导致肝细胞癌的理解直接相关。了解HBV感染的最新进展表明，发展HCC的风险与HBV DNA的血清水平成正比，而血清HBV DNA的水平降低是HBV治疗的主要治疗靶点。宿主控制肝内HBV复制的生物学机制尚未完全理解，但是更好的理解可能会导致更有效的治疗方法，从而阻止HCC的发展。我们假设肝内HBV水平受到先天免疫系统的一部分调节，该水平通过激活APOBEC蛋白质家族而导致HBV基因组的突变，并导致HOS甲基转移酶甲基甲基化HBV基因组，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的甲基化增加（对应于肝细胞癌中的甲基表型），从而导致了癌变。在AIM中，我们将确定APOBEC诱导的HBV基因组在患有慢性HBV感染的HBV基因组中的频率，并检验过超突化程度可以预测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的特异性PCR确定甲基化的频率和非集成HBV的甲基化水平，并检验HBV DNA的甲基化水平的假说是肝内HBV水平的鉴定。我们还测试了人类细胞可以直接甲基化HBV DNA并研究负责的甲基转移酶的假设。在AIM三中，我们研究了HBV相关的HCC，以探讨它们将证明肿瘤抑制基因甲基化水平增加的假设。这些研究将大大提高我们的理解，并有可能治疗HCC。该建议研究了先天免疫系统的某些元素如何通过病毒DNA的遗传和表观遗传学修饰以及先天免疫系统的这些相同元素有助于致癌。