It is well known that ethanol (EtOH) exposure damages brain tissue;however, the underlying mechanisms are not fully understood. Building on our recent work that the newly discovered cell death- mediator, transforming growth factor-?-inducible early gene 2 (TIEG2) protein, is significantly increased by alcohol in human brain cells and also in adult rat brains, the objective of this innovative proposal is to further characterize the role of TIEG2 in EtOH-induced brain damage. TIEG2 is a transcription factor that inhibits cell growth, induces apoptosis, and increases the expression of monoamine oxidase B (MAO B). The enzymatic activity of MAO B generates H2O2, a major cause of reactive oxygen species (ROS) toxicity. EtOH reportedly increases the activity of MAO B, and secondarily increases the production of H2O2. Our published data show that physiologically-relevant EtOH increases the expression of the TIEG2-MAO B pathway in a neuronal cell line. Over-expression of TIEG2 enhances, whereas inhibitors of MAO B reduce EtOH-induced neuronal death. Additionally, a frequent TIEG2 gene variant (Gln62Arg, a polymorphism of TIEG2) alters the activity of TIEG2 and renders cells more sensitive to oxidative stress than the TIEG2 wild type. Therefore, we hypothesize that ethanol induces the expression of TIEG2 and its variant (the MAO B transcriptional activators). Secondly, we hypothesize that inhibitors of MAO B may provide protection against ethanol-induced brain tissue injury by reducing the TIEG2-MAO B- produced reactive oxygen species (ROS).
Our Specific Aims are (1) To identify the molecular signaling components involved in ethanol-induced up-regulation of TIEG2;(2) To determine whether the TIEG2 gene variant (Gln62Arg) sensitizes cells to ethanol toxicity more than the TIEG2 wild type;(3) To determine the protective effects of MAO B inhibitors on cellular survival against ethanol-induced toxicity;and (4) To examine the protective effects of MAO B inhibitors on ethanol-induced neurotoxicity in adult rat brain tissues. The levels of TIEG2, MAO B, and cell death markers will be determined by quantitative real-time RT- PCR, Western blot and TUNEL assays, respectively. The cell proliferation rate, the production of ROS, and the neurodegeneration will also be determined. A comparison will be made among different groups: untreated controls;ethanol-treated;MAO B inhibitor-treated;and ethanol-treated accompanied with MAO B inhibitors. Our proposal will examine the potential role of a novel pathway involving TIEG2 and MAO B in EtOH- induced neurotoxicity and identifies a genetic risk factor that may confer susceptibility to ethanol-induced brain cell damage. It will also serve as the translational study for developing new antioxidant therapeutics for ethanol-induced brain tissue injury. Therefore, this proposal has the potential to greatly impact public health.

Public Health Relevance

Approximately 10 million alcoholics in the United States suffer from mild to severe neuropsychological difficulties as a result of brain damage caused by drinking;however, no effective treatments have been developed because the pathological mechanisms by which alcohol affects the brain are unknown. Recently, we discovered that the cell death-mediator, TIEG2 protein, is significantly increased by alcohol in human brain cells. Our proposed studies will investigate (1) how alcohol can increase the expression of TIEG2;(2) whether the TIEG2 genetic variant is a risk factor that contributes to the wide range of alcohol-related brain damage;and (3) whether TIEG2 is a potential drug target to treat or prevent alcohol-induced brain cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020103-03
Application #
8508765
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (04))
Program Officer
Regunathan, Soundar
Project Start
2011-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$363,839
Indirect Cost
$113,261
Name
University of Mississippi Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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