Program Director/Principal Investigator (Hahn, Young S.): Project Summary: Chronic HCV infection affects an estimated 3% of the world's population (>180 million people) and is a worldwide health problem causing end-stage liver diseases including hepatocellular carcinoma (HCC). The development of HCV-related HCC occurs by advanced fibrosis or cirrhosis. The clinical outcome of HCV infection and HCC risk depends on a balance between pro- and anti-inflammatory cytokines and the severity of liver inflammation. Our preliminary data show that exosomes released from HCV-infected hepatocytes contain the immunoregulatory molecules such as TGF-?. Importantly, HCV exosmes derived from infected hepatocytes promote intercellular communication with non-parenchymal cells such as M? and LSEC. As a result of receiving signaling from HCV exosomes, M? and LSEC are differentiated into fibrotic cells, that activate stellate cells and induce the development of liver fibrosis. The overall goal of this project is to define the mechanism by which HCV-derived exosomes from infected hepatocytes drive pro-fibrotic liver microenvironment and explore potential therapeutic agents to prevent liver fibrosis.
In Aim 1, we propose to identify key molecular machinery required for the secretion of hepatocyte exosomes after HCV infection in in vitro and in vivo.
In Aim 2, we will determine how HCV-derived exosomes induce the activation of fibrotic M2-like M?.
In Aim 3, we will determine how HCV-derived exosomes induce fibrotic LSEC differentiation and explore a therapeutic strategy for preventing fibrosis. The studies proposed here will break new ground for identifying factors crucial for driving pro-fibrotic liver microenvironment and will help to develop novel therapeutic targets for the prevention of liver fibrosis. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
Cellular crosstalk is a process through a message transmitted between cells. Intercellular crosstalk of hepatocytes and non-parenchymal cells (i.e. M? and LSEC) is crucial for the maintenance of liver homeostasis. Under the pathological condition, hepatocyte damage results in the activation of fibrotic M? and LSEC. Thereby these cells play a critical role in the control of hepatic inflammation and the development of liver fibrosis. Exosomes are small membrane-bound extracellular vesicles and serve as natural carriers of signaling molecules such as cytokines for prompting cellular crosstalk. This project will identify a major cellular and molecular mechanism for the role of exosomes released from HCV-infected hepatocytes in promoting intercellular communication with non-parenchymal cells (i.e. M? and LSEC), leading to the development of liver fibrosis. The findings from our proposed research will provide a rationale basis of novel immunotherapeutic strategies that target molecules inducing pro-fibrotic factors through HCV-derived exosomes.
