Persistence of HCV-Induced Perturbations of Cellular Pathways Post DAA Cure in Advanced Liver Disease

DAA 治愈晚期肝病后 HCV 诱导的细胞通路扰动的持续存在

• 批准号: 10118278
• 负责人: STEPHEN J. POLYAK
• 金额: $ 47.85万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-07 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118278
• 关键词: 3-Dimensional; Acute; Animals; Antiviral Agents; CRISPR/Cas technology; Cell Culture Techniques; Cells; Chemicals; Chromatin Remodeling Factor; Chronic; Clinical; Communication; Data; Data Set; Development; Diet; Drug Targeting; Drug usage; Epigenetic Process; Europe; Excision; France; Gene Expression; Gene Expression Profile; Genes; Genetic; Geography; Hepatic; Hepatitis C; Hepatitis C Antiviral; Hepatitis C Therapy; Hepatitis C virus; High Fat Diet; Human; Immune Targeting; Immunology; Interferon-alpha; Interferons; Internet; Knockout Mice; Liver; Liver diseases; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mediating; Microfluidics; Modeling; Modification; Molecular; Monitor; Mus; Operative Surgical Procedures; Outcome; Oxidative Stress; Paper; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Polymerase; Primary carcinoma of the liver cells; Problem Solving; Proteins; Publishing; Reader; Recurrence; Regimen; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Ribavirin; Risk; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Slice; System; Systems Biology; Technology; Testing; Time; Tissues; Validation; Viral Proteins; Viremia; Virus; Virus Diseases; Visit; Western Blotting; Work; base; cancer therapy; cell growth; clinically actionable; disorder risk; experience; experimental study; genetic approach; hepatoma cell; in vivo; innovation; insight; meetings; mouse model; overexpression; protein expression; upstream kinase; virology; virus host interaction

ABSTRACT In the era of interferon (IFN)-alpha plus ribavirin therapy, a subset of Hepatitis C Virus (HCV) infected patients were cured of their virus but some patients still developed hepatocellular carcinoma (HCC). While Directly Acting Antiviral (DAA) drugs are now able to cure the majority of HCV infections, even in subjects with advanced liver disease, what happens to liver disease upon DAA-induced cure of viremia is only beginning to emerge. After curing HCV in patients who had previously treated HCC, it has been conclusively shown that HCC recurrence does not increase. However, just like the IFN treatment era, patients with advanced liver disease still remain at risk for developing HCC even when the original insult, the virus, is eliminated by DAAs. This revised application seeks to define the molecular underpinnings for the liver disease risk that persists after DAA cure of HCV infection. Our guiding idea is that the liver remains abnormal after DAA cure of HCV. Indeed, our recently published and new preliminary data indicate that HCV-induced epigenetic, signaling and gene expression perturbations persist after DAA cure of HCV. The data derive from DAA-HCV-cure studies in cell culture, human liver slice cultures, mice, and humans. Moreover, these epigenetic changes confer changes in hepatic gene expression and signal transduction pathways known to promote liver cancer. We hypothesize that in the liver, following DAA cure of HCV, persistence of epigenetic changes activates the phosphoinositol 3 kinase (PI3K) signaling pathway to promote progression of liver disease. The hypothesis will be tested in three Specific Aims that will deploy HCV-infectivity studies on human hepatoma cells, a mouse model where the combination of HCV and diet induce liver disease, on 3D human liver slice cultures, and in human liver tissue. This comprehensive and complementary approach will be used to define how 1) HCV engages the epigenetic machinery, 2) DAA cure of HCV promotes PI3K signaling pathway, and 3) How the combination of virus and diet induced HCC is modulated by DAA cure of HCV infection in vivo. This R01 brings together investigators with experience in HCV-host interactions, clinical HCV virology, and liver immunology. It will provide timely insight into a clinically important issue in the new era of rapid cure of HCV infection. Potential outcomes include the addition of pathway-focused (e.g. PI3K) therapies to DAA regimens to reduce the risk of liver disease in the DAA era. Such drugs are already in development for other indications, so a clear outcome from our research may be clinically actionable.

抽象的 在干扰素 (IFN)-α 加利巴韦林治疗时代，部分丙型肝炎病毒 (HCV) 感染患者 病毒被治愈，但一些患者仍然发展为肝细胞癌（HCC）。直接行动时 抗病毒 (DAA) 药物现在能够治愈大多数 HCV 感染，即使是晚期肝病患者 病毒血症后，DAA 诱导治愈病毒血症后肝脏疾病的变化才刚刚开始出现。后 治愈既往接受过 HCC 治疗的患者的 HCV，已确凿地表明 HCC 复发 不增加。然而，正如IFN治疗时代一样，晚期肝病患者仍停留在 即使最初的损伤病毒已被 DAA 消除，仍存在发生 HCC 的风险。 该修订后的申请旨在定义肝病风险的分子基础，该风险在肝病治疗后持续存在。 DAA 治愈 HCV 感染。我们的指导思想是DAA治愈HCV后肝脏仍然存在异常。 事实上，我们最近发表的新初步数据表明，HCV 诱导的表观遗传、信号传导和 DAA 治愈 HCV 后基因表达扰动仍然存在。数据来自 DAA-HCV 治愈研究 细胞培养、人肝切片培养、小鼠和人类。此外，这些表观遗传变化带来了变化 已知促进肝癌的肝脏基因表达和信号转导途径。我们假设 在肝脏中，DAA 治愈 HCV 后，表观遗传变化的持续存在会激活 磷酸肌醇 3 激酶 (PI3K) 信号通路促进肝病进展。这 该假设将在三个具体目标中得到检验，这些目标将对人类肝癌细胞进行 HCV 感染性研究， 在 3D 人类肝脏切片培养物上，HCV 和饮食结合诱发肝脏疾病的小鼠模型， 以及在人体肝脏组织中。这种全面且互补的方法将用于定义 1) HCV 参与表观遗传机制，2) DAA 治愈 HCV 促进 PI3K 信号通路，以及 3) 病毒和饮食组合诱发的 HCC 是通过 DAA 调节的，可治愈体内 HCV 感染。 该 R01 汇集了在 HCV-宿主相互作用、临床 HCV 病毒学和肝脏方面具有丰富经验的研究人员 免疫学。它将及时洞察丙型肝炎快速治愈新时代的临床重要问题 感染。潜在的结果包括在 DAA 方案中添加以通路为中心的（例如 PI3K）疗法 DAA时代降低肝病风险。此类药物已经在针对其他适应症进行开发，因此 我们研究的明确结果可能在临床上可行。