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: 10523111
• 负责人: Alan McLachlan
• 金额: $ 35.85万
• 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/10523111
• 关键词: APC gene; Acute; Address; Anabolism; Animal Model; Anthelmintics; Antiviral Therapy; Biological Models; Capsid; Cell Culture Techniques; Cell Line; Cell Therapy; 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; Health; HepG2; Hepatitis B Infection; Hepatitis B Therapy; Hepatitis B Virus; Hepatocyte; Human; Liver; Liver Cirrhosis; Liver neoplasms; Lobule; Mediating; Mediator; Metabolism; Modality; Molecular; Mus; PI3K/AKT; PTEN gene; Pathway interactions; Pharmaceutical Preparations; Phenotype; 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; Transfection; Transgenic Mice; Variant; Viral; Viral Genome; Viral Load result; Virus Diseases; Virus Replication; antiviral drug development; beta catenin; chronic liver disease; curative treatments; drug development; gene product; glycogen synthase kinase 3 beta; hepatoma cell; histone modification; human pathogen; in vivo; inhibitor; interest; knock-down; liver cancer model; 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。 B型肝炎病毒（HBV）感染是一个世界性的健康问题。据估计 世界上有2亿到5亿HBV慢性携带者，迄今为止， 可靠的治疗。HBV引起急性和慢性肝病， 据估计，每年有100万人死于肝硬化和原发性肝细胞癌， 癌（HCC）。目前可用的疗法减少病毒载量，但未能解决 慢性HBV感染，因此需要终身治疗。的主要障碍 慢性HBV感染的解决是合适的HBV靶点数量有限， 抗病毒疗法的发展。目前所有的抗病毒治疗都是针对HBV的 逆转录酶/DNA聚合酶，往往导致耐药的发展 变体。治愈性治疗将需要确定额外的抗病毒靶点。 对HBV生物合成有重要贡献的细胞基因产物代表了 潜在的额外抗病毒靶点，其单独或与当前HBV 逆转录酶抑制剂可能代表一种潜在的治愈疗法。一个潜在 可能代表HBV抗病毒靶点的细胞基因靶点是β-连环蛋白，其末端 Wnt/β-catenin信号转导通路的介导物，其可被 FDA批准的药物，Pyrvinium初步数据表明β-连环蛋白可以被激活， 细胞培养中HBV的转录和复制以及β-连环蛋白活性与病毒感染相关 在慢性病毒感染的HBV转基因小鼠模型中， 因此，将进行细胞培养分析，以确定分子机制 介导β-catenin增强HBV的转录和复制。表征 诱导型肝特异性β-catenin-null和APC-null（β-catenin激活）HBV转基因 小鼠将表明β-连环蛋白对病毒的限制性定位的体内贡献， 生物合成到肝小叶内的中央周围肝细胞，并限制病毒 肝癌组织内的表达。此外，治疗HBV复制细胞和 转基因小鼠与Pyrvinium将表明，如果一个可用的FDA批准的药物， 调节Wnt/β-catenin信号转导通路并作为抗病毒治疗。 定义Wnt/β-连环蛋白信号转导途径在决定水平中的作用 HBV生物合成的研究可能导致细胞治疗靶点的鉴定， 适合于进一步开发新的方式来解决，而不仅仅是治疗 慢性HBV感染