An important genetic risk factor for the development of alcoholism is differential sensitivity to an acute dose of alcohol. Acute alcohol responses are a function of the combined effects of initial sensitivity and acute functional tolerance (AFT), bot of which are influenced by genetic factors. Using inbred mouse strains, we have been using a paradigm known as rapid tolerance - tolerance that develops within 24 hrs following a single exposure to alcohol - as a tool to investigate the genetics of acute alcohol responses. We have found that the Inbred Long and Short Sleep mouse strains (ILS and ISS) differ considerably in their ability to develop rapid tolerance using the loss of righting reflex test (LORR) as the measure of sensitivity. This strain- dependent difference appears to be mediated at least partly by differential effects on AFT. We hypothesize that genetic variance in rapid tolerance occurs as a result of genotype-dependent differences in baseline gene expression, in alcohol-mediated effects on gene expression, and in differences in gene sequence and structure. Thus, we propose to exploit the rapid tolerance model to examine the molecular and genetic basis of acute responses using Next Generation high-throughput deep sequencing technologies. The genetics of rapid tolerance, initial sensitivity, and AFT will be investigated using the LXS recombinant inbred (RI) mouse strain panel which was derived from the ILS and ISS. Expression profiling will be conducted using quantitative RNA sequencing (RNA-seq) with which it is possible to investigate effects on alternative splicing as well as on transcript abundance. The following six Specific Aims are being proposed: 1) determine relationships between initial sensitivity, AFT, and rapid tolerance for the LORR response in the LXS RIs;2) map quantitative trait loci (QTLs) for the responses determined in Aim 1;3) sequence the full genomes of the ILS and ISS;4) conduct expression profiling in the brains of the LXS RIs;5) map expression QTLs (eQTLs) for genes identified in Aim 4 and for genes that occur within the behavioral QTL intervals determined in Aim 2;and 6) confirm expression results for genes identified in Aims 4 and 5. We propose that the results of these experiments will offer insight into the nature of genetic variance for acute alcohol sensitivity. This in turn will contribute to a deeper understanding of genetic risk for human alcoholism.

Public Health Relevance

The initiation and maintenance of alcoholism is influenced by both environmental and genetic factors. This project aims to identify genes that influence variation in acute alcohol sensitivity, a trait that is thought to contribute to genetic risk for alcoholism. Such knowledge is essential for a complete understanding of the molecular basis of alcoholism and for the development of new or improved strategies for its treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
3R01AA016957-04S1
Application #
8371962
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Reilly, Matthew
Project Start
2007-07-01
Project End
2014-03-31
Budget Start
2012-09-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$129,895
Indirect Cost
$43,524
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Rudra, Pratyaydipta; Shi, W Jenny; Vestal, Brian et al. (2017) Model based heritability scores for high-throughput sequencing data. BMC Bioinformatics 18:143
Dowell, Robin; Odell, Aaron; Richmond, Phillip et al. (2016) Genome characterization of the selected long- and short-sleep mouse lines. Mamm Genome 27:574-586
Gritz, Stephanie M; Larson, Colin; Radcliffe, Richard A (2016) Atp1a2 contributes modestly to alcohol-related behaviors. Alcohol 56:29-37
Bennett, Beth; Larson, Colin; Richmond, Phillip A et al. (2015) Quantitative trait locus mapping of acute functional tolerance in the LXS recombinant inbred strains. Alcohol Clin Exp Res 39:611-20
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Dumas, Laura; Dickens, C Michael; Anderson, Nathan et al. (2014) Exome sequencing and arrayCGH detection of gene sequence and copy number variation between ILS and ISS mouse strains. Mamm Genome 25:235-43
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Radcliffe, Richard A; Larson, Colin; Bennett, Beth (2013) Genetic studies of acute tolerance, rapid tolerance, and drinking in the dark in the LXS recombinant inbred strains. Alcohol Clin Exp Res 37:2019-28

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