Liver fibrosis, the accumulation of extracellular matrix proteins, occurs in most types of chronic liver disease. Patients with liver fibrosis may progress to cirrhosis with subsequent portal hypertension, hepatic failure and hepatocellular carcinoma. Unfortunately, there are no effective antifibrotic treatments for patients with chronic liver disease. Activation of hepatic stellate cells (HSCs) is the central event in liver fibrogenesis. Activated HSCs are the main extracellular matrix protein producing cell type in fibrotic liver and key fibrogenic signals have been identified including signaling through toll-like receptor 4 (TLR4). All molecules required for TLR4 signaling are induced during the activation process of HSCs, rendering activated HSCs responsive to TLR4 ligands such as lipopolysaccharide (LPS) with activation of signaling pathways including NFicB and JNK, and the synthesis of pro-inflammatory molecules. TLR4 mutant mice are resistant to experimental liver fibrosis. The goal of this project is to further define the mechanisms by which TLR4 leads to liver fibrosis and to test TLR4 as a potential target of therapy via ligand-binding soluble receptors. The underlying hypotheses that serve as the basis for this proposal are the following: 1. Intracellular TLR4 adaptor proteins and effector molecules contribute differently to pro-inflammatory gene expression following LPS stimulation. 2. Other endogenous ligands including high-mobility group box 1 (HMGB1) directly interact with TLR4 and induce pro-inflammatory effects in HSCs. 3. Pro-inflammatory and fibrogenic actions can be blocked by using a soluble TLR4 receptor that modulates TLR4 signaling. We therefore wish to pursue four specific aims. We want to further define the signaling pathways and mechanisms by which TLR4 mediates its effects in HSCs (aim 1). We will investigate the effect of HMGB1 as endogenous TLR4 ligand on cultured HSCs, and in a mouse model of liver fibrosis (aim 2). We also want to determine whether other endogenous TLR4 ligands mediate hepatic fibrogenesis (aim 3). As shown in our preliminary data, we developed a soluble TLR4 receptor, which inhibits LPS induced signaling and pro-inflammatory actions in HSCs. We therefore want to extend these studies and use the soluble TLR4 receptor as preventive and therapeutic approach in animal models of liver fibrosis (aim 4). The overall goal is to gain new insights into the pathophysiology of HSCs and to provide a better understanding of the molecular mechanisms underlying chronic liver diseases. Eventually this approach might lead to a novel therapy for patients with chronic liver disease. To achieve the proposed research aims, I will gain additional expertise in sophisticated molecular biology techniques. During the time of the award I will continue basic research to study liver fibrosis with an emphasis on """"""""translational medicine"""""""" - taking the latest research and translating it into clinical therapies.
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