Liver fibrosis, the accumulation of extracellular matrix (ECM) proteins, occurs in most types of chronic liver diseases. Liver fibrosis progresses to cirrhosis with subsequent portal hypertension, hepatic failure, and hepatocellular carcinoma, Activated hepatic stellate cells (HSCs) are the major ECM producing cell in the fibrogenic liver and key fibrogenic signals have been identified, including transforming drug factor beta (TGFbeta), reactive oxygen species (ROS), and Ang II. We have demonstrated that the key signaling pathway activated by Ang II in activated HSC is the endogenous generation of ROS by NADPH oxidase and that the downstream effects module HSC proliferation, production of ECM proteins, and synthesis of inflammatory cytokines. Thus we have begun to elucidate the mechanistic relationship between inflammation, Ang II, reactive oxygen species, and hepatic fibrosis. We wish to pursue four specific aims to further characterize the role of Ang II in hepatic fibrosis and the downstream activation of NADPH oxidase. The underlying hypotheses that serve as the basis for this proposal are the following: 1.The renin-angiotensinogen system is a critical pathway in hepatic fibrosis. 2. The major mediator of the effects of Ang II including changes in gene expression is the activation of NADPH oxidase. 3. Other fibrogenic factors also induce NADPH oxidase, so that this enzyme becomes the critical mediator of the generation of reactive oxygen species and subsequent induction of fibrogenesis. 4. New insights into the mechanisms by which Ang II and NADPH oxidase mediate hepatic fibrogenesis will lead to the development of novel therapies for patients with fibrotic liver diseases.
The specific aims of the proposal are: 1. To define the components of the NADPH oxidase complex in hepatic stellic cells. 2. To assess the effect of inhibiting Ang II on hepatic fibrosis and hepatic stellate cell apoptosis. 3. To assess the effect of titrating the angiotensinogen gene in models of hepatic fibrosis. 4. To determine if other mediators of hepatic fibrosis in addition to Ang II activate NADPH oxidase.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072237-06
Application #
7624318
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2005-09-15
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
6
Fiscal Year
2009
Total Cost
$323,019
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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