During the current period of support we completed next generation sequencing (RNA-Seq) from cohorts of human brain samples obtained from the NSW Tissue Resource Center-University of Sydney. We also defined expression changes of microRNAs (miRNAs) in both human and mouse brain, proposing that miRNA act as master switches, responsible for many of the changes in gene expression changes and that a single miRNA can alter alcohol consumption. Our previous microarray studies identified potential splice variations in GABAB receptors in human alcoholics and we used RNA-Seq to discover novel, complex splicing of the GABAB1 gene in human brain and showed that chronic alcohol produces additional splicing complexity. We also used our RNA-Seq data to perform a systems network analysis on alcoholics and matched controls across brain regions (prefrontal cortex and basolateral and central amygdala) to define molecular networks based upon lifetime alcohol consumption. We then identified gene networks based on mRNA and microRNA transcriptome profiling that significantly overlap in human alcoholics and mouse models of excessive alcohol consumption. In our proposed studies, we will mine our extensive human RNA-Seq transcriptome profiles in novel and innovative ways to link gene expression changes with genetic differences found in the Collaborative Studies on Genetics of Alcoholism (COGA) studies. We will focus our efforts on identifying candidate FDA approved drugs that can be tested in mouse models of alcohol consumption.
Three Specific Aims are proposed: 1) bioinformatics analysis of next generation sequencing and genome-wide association studies will reveal human genes contributing to the risk of alcohol dependence, 2) convergent changes in gene expression between human alcoholics and mouse models of excessive alcohol consumption will be determined using network analysis of synaptoneurosome and microglia genes in the amygdala and prefrontal cortex of both species, and 3) novel therapeutics based on drugs that are in late-phase clinical trials or have existing FDA approval for other purposes will be selected and tested in alcohol drinking models in mice. Identification of effective target compounds in mice will facilitate testing in humans. The repurposing strategy has been used successfully to advance treatment for other diseases but has not been used for alcohol dependence, a disease lacking effective treatment options.

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 and strategies to identify potential alcohol treatment options using repurposed FDA approved drugs. 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 #
2R01AA012404-16A1
Application #
9102681
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Reilly, Matthew
Project Start
1999-12-01
Project End
2021-03-31
Budget Start
2016-04-10
Budget End
2017-03-31
Support Year
16
Fiscal Year
2016
Total Cost
Indirect Cost
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
McCarthy, Gizelle M; Warden, Anna S; Bridges, Courtney R et al. (2017) Chronic ethanol consumption: role of TLR3/TRIF-dependent signaling. Addict Biol :
Harris, R Adron; Bajo, Michal; Bell, Richard L et al. (2017) Genetic and Pharmacologic Manipulation of TLR4 Has Minimal Impact on Ethanol Consumption in Rodents. J Neurosci 37:1139-1155
Mayfield, Jody; Harris, R Adron (2017) The Neuroimmune Basis of Excessive Alcohol Consumption. Neuropsychopharmacology 42:376
Mayfield, R Dayne (2017) Emerging roles for ncRNAs in alcohol use disorders. Alcohol 60:31-39
Warden, Anna S; Mayfield, R Dayne (2017) Gene expression profiling in the human alcoholic brain. Neuropharmacology 122:161-174
Warden, Anna; Truitt, Jay; Merriman, Morgan et al. (2016) Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep 6:27618
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
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
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
Warden, Anna; Erickson, Emma; Robinson, Gizelle et al. (2016) The neuroimmune transcriptome and alcohol dependence: potential for targeted therapies. Pharmacogenomics 17:2081-2096

Showing the most recent 10 out of 59 publications