Hepatitis C virus infection and mechanism of liver disease progression

丙型肝炎病毒感染及肝病进展机制

• 批准号: 9891052
• 负责人: Ranjit Ray
• 金额: $ 34.09万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891052
• 关键词: Antiviral Agents; Applications Grants; Biopsy Specimen; Chronic Hepatitis C; Disease; Disease Progression; Epithelial; Epithelium; Etiology; Face; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Goals; Growth; Hepatitis C; Hepatitis C Therapy; Hepatitis C Vaccine; Hepatitis C virus; Hepatocyte; Human; In Vitro; Infection; Liver; Liver Failure; Liver diseases; Malignant - descriptor; Malignant Neoplasms; Mediating; Mesenchymal; MicroRNAs; Molecular; Mutation; Outcome; Pathogenesis; Patients; Phenotype; Preventive; Primary Infection; Primary carcinoma of the liver cells; Process; Regulation; Relapse; Role; Signal Pathway; Testing; Viral; Viral Proteins; base; cell growth; cell transformation; chronic infection; citrate carrier; cost; effective therapy; improved; improved outcome; liver biopsy; novel; novel therapeutics; stem-like cell; treatment strategy; tumor; virus infection mechanism

Abstract Hepatitis C virus (HCV) often causes persistent infection, and is an increasingly important factor in the etiology of hepatocellular carcinoma (HCC). There is no preventive or therapeutic hepatitis C vaccine available. Direct antiviral agents have significantly improved outcome of HCV infection, although it does not prevent reinfection. Further, the treatment is costly and already faces new issues, such as viral mutation. Recent studies suggested that some patients still progress to liver failure and/or cancer despite being cured of infection after therapy. Therefore, studies are extremely urgent to understand the underlying mechanisms of HCV associated liver pathogenesis. We and others have shown transcriptional regulatory activities of hepatitis C proteins on a number of cellular genes, which may form the genetic basis for malignant transformation of infected hepatocytes. Since hepatitis C causes silent disease initially, we do not know when infected cells transform and who the players are along with viral proteins. Thus, our overall goal in this grant application is to delineate the mechanisms of hepatitis C mediated HCC. We observed that hepatitis C modulates microRNAs (miRNA) that can influence hepatocyte growth. We recently observed that hepatitis C infection of primary human hepatocytes induces phenotypic changes by enhancing epithelial mesenchymal transition (EMT) related gene expression, and generates tumor initiating stem-like cells (TISCs). Based on the novel information, we hypothesize that hepatitis C modulates miRNAs and signaling pathways concurrently to promote hepatocyte growth, leading to HCC progression. We will validate our key observations using liver biopsy specimens from hepatitis C infected patients to maintain human relevance. Examining essential steps for inhibition will open up new avenues for developing effective treatment strategies against this highly prevalent disease.

摘要 丙型肝炎病毒（HCV）经常引起持续感染，并且是丙型肝炎的一个越来越重要的因素。 肝细胞癌（HCC）的病因学。没有预防或治疗丙型肝炎疫苗 available.直接抗病毒药物显著改善了HCV感染的结局，尽管它并没有 防止再感染。此外，治疗费用昂贵，并且已经面临新的问题，例如病毒突变。 最近的研究表明，一些患者尽管被治愈，但仍然进展为肝功能衰竭和/或癌症。 治疗后的感染因此，了解其内在机制的研究迫在眉睫 HCV相关的肝脏发病机制。我们和其他人已经显示了转录调节活性， 丙型肝炎蛋白在许多细胞基因上，这可能构成恶性的遗传基础 感染肝细胞的转化。由于丙型肝炎最初导致沉默的疾病，我们不知道什么时候 受感染的细胞转化和谁的球员是沿着与病毒蛋白质。因此，我们的总体目标是， 应用是阐明丙型肝炎介导的HCC的机制。我们观察到丙型肝炎 调节可影响肝细胞生长的microRNA（miRNA）。我们最近观察到丙型肝炎 感染原代人肝细胞通过增强上皮间充质细胞诱导表型变化 转化（EMT）相关基因表达，并产生肿瘤起始干细胞样细胞（TISC）。基于 根据这些新的信息，我们推测丙型肝炎可以调节miRNAs和信号通路 同时促进肝细胞生长，导致HCC进展。我们将验证密钥 使用来自丙型肝炎感染患者的肝活检标本进行观察，以保持人类相关性。 检查抑制的基本步骤将为开发有效的治疗开辟新的途径 针对这种高度流行的疾病的战略。