During the current period of support, we used microarrays to define changes in gene expression in brain (prefrontal cortex and amygdala) and blood of alcoholic and non-alcoholic subjects. We have also profiled the expression of miRNAs in brain and propose that they are 'master switches,'responsible for many of the gene expression changes. In the proposed research, we will expand these findings in three areas. First, based on our preliminary studies of the GABAB receptor, we propose that regulation of some genes by chronic alcohol consumption is splice variant specific. Second, we will determine if the extent of changes in gene expression seen in human alcoholics are also present in three widely used mouse models of alcohol consumption. Because these mouse models are used for medication development, it is essential to determine the genetic factors that underlie neurochemical responses characteristic of alcoholism in these models. Third, selected miRNAs that were changed in frontal cortex of human alcoholics will be delivered to mouse brain to determine which gene networks are altered by these miRNAs. We propose that a single miRNA can produce selective changes in gene expression that change alcohol consumption.
Three Specific Aims are proposed: 1) next generation sequencing will reveal novel splice variants of differentially expressed transcripts in human brain, and subsequent RT-PCR analysis will define splice-specific regulation of gene expression in alcoholism, 2) some expression changes in functional groups of genes found in the amygdala and frontal cortex of human alcoholics will be seen in these same brain regions using mouse models of excessive alcohol consumption, and 3) overexpression of select miRNAs in mouse brain will alter drinking phenotypes, and these changes will be correlated with specific patterns of gene expression in the prefrontal cortex and amygdala.

Public Health Relevance

We propose that alcohol-induced changes in brain function are due to alterations in gene expression and we will explore these changes with several innovative approaches to alcohol research, including next generation sequencing of selected brain transcripts and delivery of alcohol-related miRNAs to brain. This work will provide new opportunities for gene-based diagnosis and treatment of alcohol dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA012404-13
Application #
8425098
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Murray, Gary
Project Start
1999-12-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
13
Fiscal Year
2013
Total Cost
$366,477
Indirect Cost
$126,178
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
Most, Dana; Leiter, Courtney; Blednov, Yuri A et al. (2016) Synaptic microRNAs Coordinately Regulate Synaptic mRNAs: Perturbation by Chronic Alcohol Consumption. Neuropsychopharmacology 41:538-48
Mayfield, J; Arends, M A; Harris, R A et al. (2016) Genes and Alcohol Consumption: Studies with Mutant Mice. Int Rev Neurobiol 126:293-355
Wolfe, Sarah A; Workman, Emily R; Heaney, Chelcie F et al. (2016) FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties. Nat Commun 7:12867
Farris, S P; Arasappan, D; Hunicke-Smith, S et al. (2015) Transcriptome organization for chronic alcohol abuse in human brain. Mol Psychiatry 20:1438-47
Osterndorff-Kahanek, Elizabeth A; Becker, Howard C; Lopez, Marcelo F et al. (2015) Chronic ethanol exposure produces time- and brain region-dependent changes in gene coexpression networks. PLoS One 10:e0121522
Farris, Sean P; Pietrzykowski, Andrzej Z; Miles, Michael F et al. (2015) Applying the new genomics to alcohol dependence. Alcohol 49:825-36
Booth Depaz, Iris M; Toselli, Francesca; Wilce, Peter A et al. (2015) Differential expression of cytochrome P450 enzymes from the CYP2C subfamily in the human brain. Drug Metab Dispos 43:353-7
Toselli, Francesca; Booth Depaz, Iris M; Worrall, Simon et al. (2015) Expression of CYP2E1 and CYP2U1 proteins in amygdala and prefrontal cortex: influence of alcoholism and smoking. Alcohol Clin Exp Res 39:790-7
Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2015) Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans. Alcohol Clin Exp Res 39:136-45
Most, D; Ferguson, L; Blednov, Y et al. (2015) The synaptoneurosome transcriptome: a model for profiling the emolecular effects of alcohol. Pharmacogenomics J 15:177-88

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