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Abstract
Grant Number: 1R01AA015055-01 Project Title: Hepatic Stellate Cell Activation induced by HCV
PI Information: Name Title BRENNER, DAVID A. dbrenner@ucsd.edu CHAIRMAN Abstract: 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.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
fibrosis, hepatitis C virus, liver, liver cirrhosis, virus protein
alcoholic beverage consumption, liver cell, lymphocyte
cell line, clinical research, human tissue, laboratory rat, polymerase chain reaction, tissue /cell culture
Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES Columbia University Medical Center NEW YORK, NY 100323702 Fiscal Year: 2003 Department: MEDICINE Project Start: 30-SEP-2003 Project End: 31-AUG-2008 ICD: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM IRG: ZRG1