Ethanol consumption contributes to approximately 6% of global deaths and is a major cause of morbidity and mortality in the United States. According to NIAAA statistics, about 57% of adults report consuming alcohol recently and 25% of adults engage in binge drinking. These statistics support a pressing need for understanding the biochemical mechanisms underlying chronic and binge drinking toward the pathogenesis of alcoholic liver disease. Ethanol metabolism is known to alter numerous biochemical pathways, including glycolysis, lipid metabolism, and the TCA cycle, as well as the induction of oxidative stress. The overall concept of oxidative damage in ethanol toxicity is well known, but altered thiol redox signaling and control is an area of investigation largely underexplored in ethanol toxicity and has major implications for multiple pathologic processes, including inflammation, cell growth, and metabolism. Therefore, we present an innovative approach for investigating how alcohol-mediated induction of hepatic mitochondrial protein acetylation impacts thiol redox signaling and control. We will investigate the proposed specific aims:
Specific Aim 1 : Investigate the metabolic impact of acute ethanol toxicity on hepatic mitochondrial thiol redox signaling and control.
Specific Aim 2 : Understand the impact of chronic ethanol metabolism on hepatic mitochondrial thiol redox signaling and control.
Specific Aim 3 : Characterize the regulatory implications of ethanol metabolism on protein thiol switches.
These aims will be interrogated utilizing a multidisciplinary approach and cutting-edge targeted and untargeted ?OMICS techniques, as well as innovative data analyses and bioinformatics. Additionally, computational integration of multiple different ?OMICS datasets with other biomarkers of oxidative stress and liver damage represent a substantial intellectual innovation that will provide previously undiscovered mechanistic leads that will fuel future research aims. Lastly, understanding the mechanisms by which ethanol metabolism impacts hepatic thiol redox systems will support the development of novel therapeutic strategies to ameliorate alcoholic liver disease in millions of Americans.

Public Health Relevance

Alcohol consumption contributes to 6% of global deaths. The long-term goals of this research project are to investigate biochemical mechanisms contributing to the pathogenesis of liver disease in both acute and chronic alcohol toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA026928-01
Application #
9584899
Study Section
National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
Program Officer
Lin, Li
Project Start
2018-09-05
Project End
2020-08-31
Budget Start
2018-09-05
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045