HCV infection, cross-talk among liver cells, and liver disease progression

 描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染仍然是一个主要的全球健康问题。据估计，全球有1.8亿人感染丙型肝炎病毒，美国有400万人感染。慢性丙型肝炎病毒感染仍然是导致肝硬变和肝细胞癌的主要原因。尽管最近在直接作用抗病毒药物(DAA)方面取得了进展，但一些患者经历了终末期肝病的进展。因此，了解丙型肝炎病毒介导的肝病进展的潜在机制对于寻找新的治疗靶点是至关重要的。在我们目前的赠款期间，我们提出了几点重要的意见。我们证明，丙型肝炎病毒感染诱导自噬，以保护病毒的生长，并在多个步骤损害干扰素(干扰素)信号机制。我们还发现，丙型肝炎病毒诱导巨噬细胞分泌IL-1β，而不清除肝细胞中的病毒。此外，我们确定了一组在慢性丙型肝炎病毒感染的肝纤维化患者血清中升高的microRNAs(MiRNAs)。新出现的证据表明，外切体是新近发现的携带循环中miRNA进行细胞间通讯的载体，对它们在丙型肝炎病毒介导的肝病中的作用知之甚少。我们进一步观察到一组miRNAs在丙型肝炎病毒感染过程中在肝细胞内受到调节。根据我们的初步结果，我们推测，丙型肝炎病毒诱导的肝细胞中的miRNAs是由外切体转运到肝星状细胞(HSCs)/枯否细胞(KCs)，并在丙型肝炎病毒介导的肝脏发病机制中发挥关键作用。我们还预测，丙型肝炎病毒感染后细胞内miRNAs的调节会改变肝细胞的生长。为了验证我们的假设，我们提出了以下具体目标：(1)确定丙型肝炎病毒诱导的通过外体转运的miRNAs(exo-miR)在引起肝星状细胞激活中的作用；(2)确定丙型肝炎病毒刺激巨噬细胞/枯否细胞中的炎性细胞因子并对其他类型的肝细胞产生功能影响的机制；(3)研究丙型肝炎病毒诱导的细胞内miRNA在促进原代人肝细胞生长中的作用。了解肝细胞之间的串扰将提供丙型肝炎病毒介导的肝病进展的深入机制，并有助于确定其他治疗靶点。

 DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection remains a major global health problem. An estimated 180 million people worldwide and 4 million people in the United States are infected with HCV. Chronic HCV infection remains a major cause of cirrhosis and hepatocellular carcinoma (HCC). Despite recent advances in direct acting antivirals (DAA), some patients experience end stage liver disease progression. Thus, it is essential to understand the underlying mechanisms of HCV mediated liver disease progression for new therapeutic targets. In our current grant period, we made several important observations. We demonstrated that HCV infection induces autophagy for protection of virus growth, and impairs interferon (IFN) signaling mechanisms at multiple steps. We have also shown that HCV induces IL-1β secretion from macrophages without clearing virus from hepatocytes. Further, we identified a group of microRNAs (miRNAs) that are elevated in sera of chronically HCV-infected liver fibrosis patients. Emerging evidence suggests that exosomes are newly identified vehicle carrying circulating miRNAs for intercellular communications and little is known about their role in HCV mediated liver disease. We further observed a group of miRNAs is modulated during HCV infection within hepatocytes. Based on our preliminary results, we hypothesize that HCV induced miRNAs in hepatocytes are transported by exosomes to hepatic stellate cells (HSCs)/Kupffer cells (KCs), and play critical roles in HCV-mediated liver pathogenesis. We also predict that modulation of intracellular miRNAs following HCV infection alters hepatocyte growth. To test our hypothesis, we propose the following specific aims: (1) determine the role of HCV induced miRNAs transported through exosomes (exo-miR) in causing hepatic stellate cell activation, (2) determine the mechanism by which HCV stimulates inflammatory cytokines in macrophages/Kupffer cells and exert functional consequence on other liver cell types, and (3) investigate the role of HCV induced intracellular miRNA in primary human hepatocyte growth promotion. Understanding the cross-talk among liver cells will provide in-depth mechanism of HCV mediated liver disease progression and will help in identifying additional therapeutic targets.