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.