Chronic ethanol exposure can result in hepatic injury. This injury is exacerbated in part through an LPSdependent signaling cascade. Our lab found that chronic ethanol exposure increases the IPS response of Kupffer cells leaing to the activation LPS-induced activation of p38. Ultimately the activation of p38 will lead to TNFa mRNA stability. LPS and TNFalpha stimulate the production of reactive oxygen species. The ROS causes the redox-sensing molecule thioredoxin (Trx) to dissociate from ASK1 leading to apoptosis. Glutathione is another redox-sensing molecule that protects the cell against oxidative damage. As a result of ethanol-induced oxidative stress, mitochondrial levels of GSH drastically deplete.
The specific aims of this proposal will determine (1) effects of chronic ethanol on LPS dependent signal transduction leading to increased p38 phosphorylation (2) identify how Trx and GSH contribute to increased p38 activation in response chronic ethanol exposure (3) if overexpression of Trx-1 protects mice from ethanol-induced liver injury. Results from our studies will further our understanding of cellular antioxidant systems and possibly the prevention of ethanol-induced liver disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AA016434-01
Application #
7154969
Study Section
Special Emphasis Panel (ZAA1-HH (61))
Program Officer
Purohit, Vishnu
Project Start
2006-12-01
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
1
Fiscal Year
2006
Total Cost
$38,047
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Cohen, Jessica I; Chen, Xiaocong; Nagy, Laura E (2011) Redox signaling and the innate immune system in alcoholic liver disease. Antioxid Redox Signal 15:523-34
Cohen, Jessica I; Roychowdhury, Sanjoy; McMullen, Megan R et al. (2010) Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanol-induced liver injury in mice. Gastroenterology 139:664-74, 674.e1