Liver injury is accompanied by trans-differentiation (activation) of hepatic stellate cells (HSC) into myofibroblasts, a key event in liver fibrogenesis that results in increased proliferation and migration. These vents are accompanied by alterations in the production of extracellular matrix components required for cell- matrix interactions and excess production of scar tissue, including type I collagen and fibronectin. Thus, nhibition of HSC trans-differentiation could prevent the subsequent events leading to excess collagen deposition, fibrosis and cirrhosis. A hallmark of HSC activation is the up-regulation of platelet-derived growth factor-beta receptor (PDGF-betaR) and their increased migratory and proliferative response to PDGF-BB. Although many studies have focused on PDGF-BB-dependent molecular events leading to cell proliferation and migration, little is known regarding the role of acetaldehyde, the first metabolite of ethanol, on PDGF- betaR expression and HSC proliferation and migration. Moreover, the role of ACH and PDGF-BB on HSC- matrix interactions remains to be investigated. Based on our previous studies, namely that acetaldehyde exerts some of its action via the accumulation of reactive oxygen species (hydrogen peroxide) and the preliminary results presented in this application we propose to investigate molecular mechanismswhereby acetaldehyde modulates the expression of PDGF-betaR in HSC. We will also study the role of ACH on the migratory and proliferative responses of HSC to PDGF-BB and on the PDGF-BB-dependent alterations in cell-matrix interactions. Our long term goal is to unravel key molecular events triggered by acetaldehyde that could lead to therapeutic intervention and thus, to prevention and/or amelioration of alcohol-induced liver fibrosis and cirrhosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010541-17
Application #
7795237
Study Section
Special Emphasis Panel (ZRG1-DIG-F (02))
Program Officer
Radaeva, Svetlana
Project Start
1995-04-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
17
Fiscal Year
2010
Total Cost
$312,541
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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Lechuga, Carmen G; Hernandez-Nazara, Zamira H; Hernandez, Elizabeth et al. (2006) PI3K is involved in PDGF-beta receptor upregulation post-PDGF-BB treatment in mouse HSC. Am J Physiol Gastrointest Liver Physiol 291:G1051-61
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