Alcoholic cirrhosis continues to be a major cause of morbidity and mortality in the Western hemisphere. Its fibrogenic actions on hepatic stellate cells, the main type I collagen-producing cells in the liver, are mediated in part, by its first metabolite acetaldehyde. This compound induces the transcriptional activation of the type I collagen genes by a mechanism involving accumulation of hydrogen peroxide and up-regulation of transforming growth factor-beta (TGF-beta). However, molecular mechanisms underlying these effects remain to be elucidated. Thus, in this application we propose experiments aimed at unraveling key events triggered by acetaldehyde that will directly infringe upon collagen gene upregulation. Specifically, we propose the following aims: 1) To investigate key molecular mechanisms involved in the early response to acetaldehyde leading to COL1A2 upregulation. 2) To investigate molecular mechanisms involved in the late response to acetaldehyde leading to upregulation of TGF-beta gene expression and priming of HSC to respond more efficiently to this cytokine and 3) To study the role of acetaldehyde in the activation of latent TGF-beta in HSC. A better characterization of molecular events involved in acetaldehyde-dependent up-regulation of the type I collagen genes will allow us to establish key sites for therapeutic intervention. Moreover, from our experiments we expect to define pathways connecting acetaldehyde-mediated events with hydrogen peroxide and TGF-beta leading to the establishment of an autocrine loop that sustains fibrogenesis. Our long-term goal is to unravel molecular mechanisms involved in acetaldehyde-mediated fibrogenesis and develop novel therapies to inhibit collagen deposition and/or remove fibrous scar collagen from the liver.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA009231-12A1
Application #
6680866
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Gentry, Thomas
Project Start
1992-04-01
Project End
2007-08-31
Budget Start
2003-09-20
Budget End
2004-08-31
Support Year
12
Fiscal Year
2003
Total Cost
$342,000
Indirect Cost
Name
George Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
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