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

基本信息

批准号：
10059188
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
项目类别：
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/10059188
关键词：
APC gene Acute Address 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

项目摘要

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。据估计，乙型肝炎病毒（HBV）感染是一个世界性的健康问题。全球有 200 至 5 亿 HBV 慢性携带者，迄今为止，尚无针对他们的治疗方案。乙肝病毒可引起急性和慢性肝病，并且是可靠的治疗方法。据估计，每年有 100 万人死于肝硬化和原发性肝细胞性肝病目前可用的疗法可减少病毒载量，但无法解决问题。慢性乙型肝炎病毒感染，因此需要终生治疗，这是治疗的一个主要障碍。解决慢性乙型肝炎感染的关键是合适的乙型肝炎靶点数量有限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，通常会导致耐药性的发展治愈性疗法需要确定额外的抗病毒靶点。对 HBV 生物合成做出重大贡献的细胞基因产物代表单独或与当前 HBV 联合使用的潜在其他抗病毒靶点逆转录酶抑制剂可能是一种潜在的治疗方法。可能代表 HBV 抗病毒靶标的细胞基因靶标是 β-连环蛋白，即末端 Wnt/β-连环蛋白信号转导通路的介质，可被 FDA批准的药物Pyrvinium，初步数据表明β-catenin可以被激活。细胞培养中的 HBV 转录和复制以及 β-连环蛋白活性与病毒相关慢性病毒感染的 HBV 转基因小鼠模型体内的生物合成。经过测试，将进行细胞培养分析以确定分子机制介导 β-连环蛋白增强 HBV 转录和复制的表征。诱导型肝脏特异性 β-连环蛋白缺失和 APC 缺失（β-连环蛋白激活）HBV 转基因小鼠将表明β-连环蛋白对病毒限制性定位的体内贡献肝小叶内中央周围肝细胞的生物合成和限制性病毒 HCC 组织内的表达。此外，治疗 HBV 复制细胞和含有吡维铵的转基因小鼠将表明 FDA 批准的可用药物是否可以调节 Wnt/β-catenin 信号转导通路并起到抗病毒治疗的作用。定义 Wnt/β-连环蛋白信号转导途径在确定水平中的作用乙肝病毒生物合成的研究可能有助于确定细胞治疗靶点适合进一步发展新的方式来解决而不是简单地治疗慢性乙型肝炎病毒感染。