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: 9323675
• 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/9323675
• 关键词: Antiviral Agents; Applications Grants; Biopsy Specimen; Chronic Hepatitis C; Disease; Disease Progression; Epithelial; Etiology; Face; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Goals; Growth; Hepatitis C; Hepatitis C Therapy; 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; Tumor Initiators; Vaccines; Viral; Viral Proteins; base; cell growth; cell transformation; citrate carrier; cost; effective therapy; improved; improved outcome; liver biopsy; novel; novel therapeutics; stem-like cell; treatment strategy

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.

抽象的 丙型肝炎病毒（HCV）通常会引起持续感染，并且是越来越重要的因素 肝细胞癌（HCC）的病因。没有预防或治疗性丙型肝炎疫苗 可用的。直接抗病毒药已显着改善HCV感染的结果，尽管它没有 防止重新感染。此外，治疗是昂贵的，已经面临新问题，例如病毒突变。 最近的研究表明，尽管治愈了一些患者，但仍会发展为肝衰竭和/或癌症。 治疗后感染。因此，研究非常迫切地了解基本机制 HCV相关的肝脏发病机理。我们和其他人显示了转录调节活动的 许多细胞基因上的丙型肝炎蛋白，这可能构成恶性肿瘤的遗传基础 感染肝细胞的转化。由于丙型肝炎最初会引起无声疾病，因此我们不知道何时 感染的细胞会转化以及玩家与病毒蛋白在一起的人。因此，我们在这笔赠款中的总体目标 应用是描述丙型肝炎介导的HCC的机制。我们观察到乙型肝炎 调节可以影响肝细胞生长的microRNA（miRNA）。我们最近观察到丙型肝炎 原发性肝细胞的感染通过增强上皮间质诱导表型变化 过渡（EMT）相关的基因表达，并产生肿瘤引发的干细胞（TISC）。基于 新信息，我们假设乙型肝炎调节miRNA和信号通路 同时促进肝细胞生长，导致HCC的发展。我们将验证我们的钥匙 使用肝炎感染患者的肝活检标本进行观察以维持人类的相关性。 检查抑制基本步骤将为开发有效治疗的新途径 反对这种高度普遍疾病的策略。