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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK079015-03
Application #
7882301
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2008-07-15
Project End
2013-12-30
Budget Start
2010-07-01
Budget End
2013-12-30
Support Year
3
Fiscal Year
2010
Total Cost
$153,098
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Howe, Cody; Kim, Su Jin; Mitchell, Jonathon et al. (2018) Differential expression of tumor-associated genes and altered gut microbiome with decreased Akkermansia muciniphila confer a tumor-preventive microenvironment in intestinal epithelial Pten-deficient mice. Biochim Biophys Acta Mol Basis Dis 1864:3746-3758
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Choi, Yoon Jeong; Jung, Jane; Chung, Hyo Kyun et al. (2013) PTEN regulates TLR5-induced intestinal inflammation by controlling Mal/TIRAP recruitment. FASEB J 27:243-54
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Choi, Yoon Jeong; Im, Eunok; Chung, Hyo Kyun et al. (2010) TRIF mediates Toll-like receptor 5-induced signaling in intestinal epithelial cells. J Biol Chem 285:37570-8
Choi, Yoon Jeong; Im, Eunok; Pothoulakis, Charalabos et al. (2010) TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5. J Biol Chem 285:21382-90
Ma, Elise L; Choi, Yoon Jeong; Choi, Jinyoung et al. (2010) The anticancer effect of probiotic Bacillus polyfermenticus on human colon cancer cells is mediated through ErbB2 and ErbB3 inhibition. Int J Cancer 127:780-90
Im, Eunok; Rhee, Sang Hoon; Park, Yong Seek et al. (2010) Corticotropin-releasing hormone family of peptides regulates intestinal angiogenesis. Gastroenterology 138:2457-67, 2467.e1-5

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