Alcohol-induced liver cirrhosis is one of the major causes of death worldwide. Strong evidence has established that acetaldehyde, ethanol's first metabolite, is fibrogenic per e and enhances type I collagen production by hepatic stellate cells. Despite major efforts by several laboratories, relatively little is known pertaining the molecular events underlying this stimulatory effect. Thus, it is our long-term goal to integrate cellular and molecular events into a unified picture that explains how acetaldehyde stimulates type I collagen gene transcription in the liver.
The specific aims of this proposal: 1) To characterize the cis-regulatory elements and trans-acting factors, active in hepatic stellate cells of human origin, mediating acetaldehyde-induced human alpha2(I) collagen gene up-regulation; 2) To elucidate key molecular mechanisms by which acetaldehyde modulates the activity and/or binding of the transcription factors that interact with the acetaldehyde- responsive element of the human alpha2(I) collagen gene; and 3) To determine whether acetaldehyde stimulates human alpha2(I) collagen gene expression directly, or through an autocrine loop involving enhanced production and/or activation of transforming growth factor-beta in human hepatic stellate cells. A better characterization of the molecular events underlying enhanced COL1A2 gene expression in hepatic stellate cells, will enhance our understanding of the pathophysiology of ethanol- induced liver fibrosis, and will allow in the near future, to develop new therapies aimed at counteracting the devastating effects of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012196-03
Application #
6371547
Study Section
Special Emphasis Panel (ZRG1-ALTX-1 (01))
Program Officer
Purohit, Vishnu
Project Start
1999-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$178,562
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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