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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)：这项建议研究了某些先天免疫系统元素如何通过对病毒DNA的遗传和表观遗传修饰来调节肝组织中的乙肝病毒DNA水平，以及这些相同的先天免疫系统元素如何促进癌症的发生。这一建议直接关系到扩大我们对慢性乙肝感染如何导致肝细胞癌的理解。近年来对乙肝病毒感染认识的进展表明，发生肝细胞癌的风险与血清HBVDNA水平成正比，降低血清HBVDNA水平是治疗HBVDNA的主要目标。宿主控制肝内乙肝病毒复制的生物学机制仍不完全清楚，但更好的了解可能会导致更有效的治疗方法，以防止肝细胞癌的发展。我们假设，肝内乙肝病毒水平部分受先天免疫系统部分调节，先天免疫系统通过激活APOBEC蛋白家族导致乙肝病毒基因组突变，宿主甲基转移酶甲基化乙肝病毒基因组，导致乙肝病毒基因表达减少。我们进一步假设，这些机制通过导致肿瘤抑制基因(对应于肝细胞癌中的甲基化表型)甲基化增加而促进癌症的发生。在第一个目标中，我们将确定APOBEC在慢性乙肝病毒感染的肝脏中诱导的HBVDNA超突变的频率，并检验高突变的程度预测HBVDNA水平的假设。在第二个目标中，我们将使用定性和定量甲基化特异性聚合酶链式反应来确定非整合型乙肝病毒的甲基化频率和定量甲基化水平，并检验HBVDNA甲基化水平预测肝内乙肝病毒水平的假设。我们还测试了人类细胞可以直接甲基化HBVDNA的假设，并调查了相关的甲基转移酶。在第三个目标中，我们研究了与乙肝病毒相关的肝癌细胞，以探索它们将证明肿瘤抑制基因甲基化水平增加的假设。这些研究将极大地提高我们对肝细胞癌的认识，并有可能提高我们治疗肝细胞癌的能力。这项建议研究了先天免疫系统的某些元素如何通过对病毒DNA的遗传和表观遗传修饰来调节肝组织中的乙肝病毒DNA水平，以及这些相同的先天免疫系统元素如何促进癌症的发生。