The goal of this application Is to maintain transgenic knockout animal models that are unique and have high relevance to alcohol research. Alcohol-induced toxicity commonly Involves oxidative stress. Ethanol metabolism by microsomal and mitochondrial systems generates reactive oxygen species and reactive nitrogen species, and is associated with diminished glutathione (GSH) and antioxidant enzymatic activity. In addition, the accumulation of ethanol-derived aldehydes and hydroxyethyl radical serves to modify critical biological functions by forming adducts with proteins and DNA. The availability of animal models in which ethanol metabolism or antioxidant mechanisms are genetically modified will facilitate investigation of the role these enzymes and oxidative stress In diseases associated with ethanol consumption. Therefore, we propose:
Specific Aim 1 : To maintain the populations of existing mouse models in our laboratory so that they are readily available to researchers. Our current models include: a) the conventlonal7 /c(/77af, Aldhlbl, Aldh2, Cat, Cyp2e1, Adhi and Gclm single knockouts, b) the Cat/Cyp2e1 double knockout, and c) the hepatocyte-specific Gclc^^ knockout and the conditional Gclc '^floxed strain.
Specific Aim 2 : To generate (and maintain) unique additional mouse knockout models so that they are readily available to researchers. These Include: a) Cyp2e1/Adh1, Cat/Cyp2e1, Cat/Adhi and Cat/Cyp2e1/Adh1 triple knockout, b) Aldhlal/Aldhlbl, Aldh1b1/Aldh2 and the Aldh1a1/Aldh1b1/Aldh2 triple knockout strains, and c) Gclm/Cyp2e1 and Gclm/Aldhlal double knockout strains. Our overarching aim Is to make valuable transgenic animal models available to the larger research community. It is expected that enhanced access to such models will accelerate our understanding of the mechanisms underlying alcohol-Induced disease and the pathophysiological effects of acute and chronic alcohol consumption. Such knowledge would facilitate the development of more effective treatments of alcohol abuse.

Public Health Relevance

Alcohol-Induced toxicity is associated with oxidative stress resulting from ethanol metabolism that generates reactive oxygen species and Is associated with reduced glutathione (GSH). The goal of this application Is to maintain and expand animal models with genetic defects In alcohol metabolizing enzymes and In GSH synthesizing enzymes that will become available to the research community.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Resource-Related Research Projects (R24)
Project #
5R24AA022057-02
Application #
8603827
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Jung, Kathy
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
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