Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis

肝小叶分区、肝细胞癌 (HCC) 和 β-连环蛋白介导的乙型肝炎病毒 (HBV) 生物合成

• 批准号: 9884339
• 负责人: Alan McLachlan
• 金额: $ 36.58万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884339
• 关键词: Acute; Address; Adenomatous Polyposis Coli; Anabolism; Animal Model; Anthelmintics; Antiviral Agents; Antiviral Therapy; Biological Models; Capsid; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Chronic; Chronic Hepatitis B; DNA Methylation; DNA-Directed DNA Polymerase; Data; Development; Drug resistance; Epigenetic Process; Evaluation; FDA approved; Gene Targeting; Genes; Genetic Transcription; Goals; Grant; Health; HepG2; Hepatitis B Virus; Hepatocyte; Human; Lead; Liver; Liver Cirrhosis; Liver neoplasms; Lobule; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Metabolism; Modality; Molecular; Mus; PI3K/AKT; PTEN gene; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Primary carcinoma of the liver cells; RNA; RNA-Directed DNA Polymerase; Regulation; Resolution; Reverse Transcriptase Inhibitors; Reverse Transcription; Role; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Tamoxifen; Tissues; Transcription Coactivator; Transgenic Mice; Variant; Viral; Viral Genome; Viral Load result; Virus Diseases; Virus Replication; base; beta catenin; chronic liver disease; curative treatments; drug development; gene product; hepatoma cell; histone modification; human pathogen; in vivo; inhibitor/antagonist; interest; knock-down; man; mouse model; mutant; novel; polypeptide; targeted cancer therapy; targeted treatment; therapeutic target; transcription factor; tumor; tumor initiation

Project Summary and Relevance. Hepatitis B virus (HBV) infection is a worldwide health problem. It is estimated that there are 200 to 500 million HBV chronic carriers in the world for whom, to date, there is no reliable treatment. HBV causes both acute and chronic liver disease and is responsible for an estimated one million deaths annually from liver cirrhosis and primary hepatocellular carcinoma (HCC). Currently available therapies reduce viral loads but fail to resolve chronic HBV infections and hence require lifelong treatment. A major obstacle to the resolution of chronic HBV infections is the limited number of HBV targets that are suitable for the development of antiviral therapies. All the current antiviral therapies target the HBV reverse transcriptase/DNA polymerase, often leading to the development of drug-resistant variants. Curative therapies will require the identification of additional antiviral targets. Cellular gene products that make a significant contribution to HBV biosynthesis represent potential additional antiviral targets which alone or in combination with current HBV reverse transcriptase inhibitors may represent a potential curative therapy. One potential cellular gene target that might represent an HBV antiviral target is β-catenin, the terminal mediator of the Wnt/β-catenin signal transduction pathway which can be inhibited by the FDA-approved drug, Pyrvinium. Preliminary data indicate that β-catenin can activated HBV transcription and replication in cell culture and β-catenin activity correlates with viral biosynthesis in vivo in the HBV transgenic mouse model of chronic viral infection. Consequently, cell culture analysis will be performed to define the molecular mechanisms mediating β-catenin enhanced HBV transcription and replication. Characterization of inducible liver-specific β-catenin-null and APC-null (β-catenin activated) HBV transgenic mice will indicate the in vivo contribution of β-catenin to the restricted localization of viral biosynthesis to pericentral hepatocytes within the liver lobule and restricted viral expression within HCC tissue. Furthermore, treatment of HBV replicating cells and transgenic mice with Pyrvinium will indicate if an available FDA approved drug can modulate the Wnt/β-catenin signal transduction pathway and act as an antiviral therapy. Defining the role of the Wnt/β-catenin signal transduction pathway in determining the level of HBV biosynthesis may lead to the identification of cellular therapeutic targets that are amenable to the further development of novel modalities to resolve rather than simply treat chronic HBV infection.

项目摘要和相关性。 乙肝病毒感染是一个世界性的健康问题。据估计，那里有 世界上有2亿到5亿慢性乙肝病毒携带者，到目前为止，还没有 可靠的治疗方法。乙肝病毒会引起急性和慢性肝病，并与 每年估计有一百万人死于肝硬变和原发性肝细胞癌 癌症(HCC)。目前可用的治疗方法可以减少病毒载量，但无法解决 慢性乙肝病毒感染，因此需要终生治疗。一个主要的障碍是 慢性乙肝病毒感染的解决是有限数量的适合的乙肝病毒靶标 用于开发抗病毒疗法。目前所有的抗病毒疗法都针对乙肝病毒。 逆转录酶/DNA聚合酶，常导致耐药发展 变种。根治疗法将需要确定更多的抗病毒靶点。 对乙肝病毒生物合成做出重大贡献的细胞基因产品代表 单独或与当前的乙肝病毒结合的潜在的额外抗病毒靶点 逆转录酶抑制剂可能是一种潜在的治疗方法。一种潜力 可能代表乙肝病毒抗病毒靶点的细胞基因靶点是β-连环蛋白，它是末端 Wnt/β-连环蛋白信号转导通路的介体，可被 FDA批准的药物，吡喃。初步数据表明β-连环蛋白可以被激活 乙肝病毒在细胞培养中的转录和复制及β-连接素活性与病毒的相关性 慢性病毒感染转基因小鼠体内生物合成研究。 因此，将进行细胞培养分析以确定分子机制。 介导β-连环蛋白促进乙肝病毒转录和复制。特征描述 可诱导的肝脏特异性β-连环蛋白缺失和β-连环蛋白激活的乙肝病毒转基因 小鼠将提示β-连环蛋白在体内对病毒的限制性定位的贡献 肝小叶和限制性病毒对中心周围肝细胞的生物合成 在肝细胞癌组织中表达。此外，治疗乙肝病毒复制细胞和 含有吡喃的转基因小鼠将表明FDA批准的现有药物是否可以 调节Wnt/β-Catenin信号转导通路，发挥抗病毒治疗的作用。 确定Wnt/β-连环蛋白信号转导通路在决定水平中的作用 乙肝病毒生物合成的研究可能导致识别细胞治疗靶点 服从于进一步发展解决而不是简单地治疗的新模式 慢性乙肝病毒感染。