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：
10297857
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
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/10297857
关键词：
APC gene Acute Address Anabolism Animal Model Anthelmintics 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 Infection Hepatitis B Virus Hepatocyte Human Lead Liver Liver Cirrhosis Liver neoplasms Lobule 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 antiviral drug development base beta catenin chronic liver disease curative treatments drug development gene product 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

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。丙型肝炎病毒（HBV）感染是全球健康问题。据估计在那里世界上有200至5亿HBV慢性运营商，迄今为止，没有可靠的治疗。 HBV引起急性和慢性肝病，是负责的估计每年死于肝硬化和原发性肝细胞的死亡癌（HCC）。目前可用的疗法减少病毒载荷但无法解决慢性HBV感染，因此需要终身治疗。一个主要障碍慢性HBV感染的分辨率是合适的HBV靶标数量有限用于开发抗病毒疗法。所有当前的抗病毒疗法针对HBV 逆转录酶/DNA聚合酶，通常导致抗药性变体。治疗疗法将需要鉴定其他抗病毒靶标。对HBV生物合成做出重大贡献的细胞基因产物代表潜在的其他抗病毒靶标，该靶标的靶标的靶标的于单独或与电流HBV结合逆转录酶抑制剂可能代表潜在的治疗疗法。一个潜力可能代表HBV抗病毒靶靶的细胞基因靶标是β-catenin，末端 Wnt/β-catenin信号转移途径的介体，可以抑制 FDA批准的药物，p基林。初步数据表明β-catenin可以激活细胞培养和β-catenin活性中的HBV转录和复制与病毒相关慢性病毒感染的HBV转基因小鼠模型中的生物合成。因此，将进行细胞培养分析以定义分子机制介导β-catenin增强了HBV转录和复制。表征诱导肝特异性β-catenin-null和APC-NULL（β-catenin激活）HBV转基因小鼠将表明β-catenin对病毒的限制定位的体内贡献生物合成与肝小叶中腹膜肝细胞的生物合成和病毒限制 HCC组织内的表达。此外，治疗HBV复制细胞和带有吡格菌的转基因小鼠将指示是否可以使用可用的FDA批准的药物调节Wnt/β-catenin信号转移途径并充当抗病毒疗法。定义Wnt/β-catenin信号转移途径在确定水平中的作用 HBV生物合成可能会导致鉴定细胞治疗靶点可以进一步发展新型方式来解决，而不是简单地对待慢性HBV感染。