Hepatic Stellate Cell Activation induced by HCV

描述（由申请人提供）：丙型肝炎病毒（HCV）感染是美国慢性肝病的主要原因。目前的抗病毒治疗只能治愈一半患者的感染。剩余的患者通常发展为进行性肝纤维化，导致肝硬化和肝细胞癌。这些患者对酒精的肝毒性作用很敏感，因为适度饮酒会加速纤维化的进展。不幸的是，慢性肝病患者没有有效的抗纤维化治疗方法。该项目的总体目标是确定HCV导致肝纤维化的机制，并确定潜在的治疗靶点。我们还将研究饮酒加重丙型肝炎影响的机制。我们将使用最近开发的工具在小鼠肝脏和肝细胞中表达HCV，并建立一个具有良好特征的酒精性肝损伤模型。这一建议基于几个潜在的假设：1)HCV直接与肝星状细胞（主要的纤维化细胞类型）相互作用，诱导肝纤维化；2)表达HCV复制子的肝细胞的成纤维产物在造血干细胞中诱导成纤维作用；3)酒精诱导表达HCV全基因组的转基因小鼠肝纤维化的发生；(4)从HCV诱导的肝硬化患者中分离的hsc表现出活化的hsc的表型和功能特征，患者的非实质肝细胞被HCV感染。本项目的具体目的是：1)确定HCV蛋白是否诱导原代培养的hsc纤维化；2)检测表达HCV的肝细胞和淋巴细胞是否诱导造血干细胞纤维化；3)探讨饮酒加重丙型肝炎肝纤维化的机制；4)探讨HCV诱导的肝硬化患者造血干细胞的表型和功能特征，以及患者非实质肝细胞是否被HCV感染。实验设计将使用造血干细胞的原代培养，表达HCV基因组复制子的培养细胞，以及在肝脏中表达整个HCV基因组的转基因小鼠。通过结合体内和体外研究，我们的目标是发现hcv诱导肝纤维化的分子发病机制的新见解。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection is the main cause of chronic liver diseases in the US. Current antiviral treatments only cure the infection in half of the patients. The remaining patients often develop progressive hepatic fibrosis, leading to cirrhosis and hepatocellular carcinoma. These patients are sensitive to the hepatotoxic effects of alcohol, since moderate alcohol consumption accelerates fibrosis progression. Unfortunately, there are no effective antifibrotic treatments for patients with chronic liver diseases. The overall goal of this project is to define the mechanisms by which HCV leads to liver fibrosis and to identify potential targets of therapy. We will also investigate the mechanisms by which alcohol consumption aggravates the effects of HCV. We will use recently developed tools to express the HCV in the mouse liver and in liver cells and a well-characterized model of alcohol-induced liver injury. This proposal is based on several underlying hypotheses: 1) HCV directly interacts with hepatic stellate cells (HSCs), the main fibrogenic cell type, to induce liver fibrosis; 2) Fibrogenic products from hepatocytes expressing the HCV replicon induce fibrogenic actions in HSCs; 3) Alcohol administration induces the development of liver fibrosis in transgenic mice expressing the whole HCV genome; and 4) HSCs isolated from patients with HCV induced liver cirrhosis show phenotypical and functional features of activated HSCs and non-parenchymal liver cells are infected by HCV in patients. The specific aims to be addressed in this project are: 1) To determine whether HCV proteins induce fibrogenic actions in primary cultured HSCs; 2) To determine whether hepatocytes and lymphocytes expressing the HCV induce fibrogenic actions in HSCs; 3) To investigate the mechanisms by which alcohol consumption aggravates HCV-induced liver fibrosis; and 4) To investigate the phenotypical and functional features of HSCs isolated from patients with HCV-induced liver cirrhosis and whether non-parenchymal liver cells are infected by HCV in patients. The experimental design will use primary cultures of HSCs, cultured cells expressing the HCV genomic replicon, and transgenic mice expressing the whole HCV genome in the liver. By combining in vivo and in vitro studies, our goal is to discover new insights into the molecular pathogenesis of HCV-induced liver fibrosis.