Alcoholism is a complex disorder caused by the influences of multiple genes, the environment, and interactions among them. The long-term goal of our studies is to provide targets for alcohol treatment by identifying genes that influence alcohol-drinking behavior. The objective of this proposal is to further study the two candidate genes, Neuropeptide Y (Npy) and Alpha-synuclein (Snca), underlying the Chromosome 4 quantitative trait locus (QTL) and previously identified to be differentially expressed in the inbred alcohol preferring (iP) and non-preferring (iNP) rats, to fine map the QTL to 2 cM, and to define other strong differentially expressed candidate genes in this fine mapped region. The proposal will employ inbred and congenic rat models for investigating the known and predicted genes in the QTL region. To study the effect of alcohol on the expression of Npy and Snca in discrete brain regions, mRNA and protein levels will be compared between the iP and iNP strains employing quantitative Real Time PCR (qRT-PCR) and Western blots, respectively. The functional significance of novel polymorphisms we identified in the Npy and Snca genes will be determined by transient transfection reporter assays. The proposal to narrow the Chr 4 QTL region to 2 cM will be accomplished by creating interval-specific congenic strains. Congenic strains, P.NP and NP.P, will be backcrossed to the respective inbred iP or iNP strain to identify animals recombinant within the map of markers placed at approximately 1 cM intervals throughout the QTL region. To identify other potential candidate genes in this region, microarray analysis will be employed as a means to identify those genes that are differentially expressed between the congenic and inbred lines. Those genes that are not only differentially expressed but are also in the narrowed 2 cM region will then be further confirmed using qRT-PCR. These experiments will combine an outstanding animal model of alcoholism and molecular techniques to provide a comprehensive approach that will identify with certainty candidate genes that influence alcohol drinking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010707-12
Application #
7253437
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Neuhold, Lisa
Project Start
1995-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
12
Fiscal Year
2007
Total Cost
$321,078
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Spence, John Paul; Reiter, Jill L; Qiu, Bin et al. (2018) Estrogen-Dependent Upregulation of Adcyap1r1 Expression in Nucleus Accumbens Is Associated With Genetic Predisposition of Sex-Specific QTL for Alcohol Consumption on Rat Chromosome 4. Front Genet 9:513
Qiu, Bin; Luczak, Susan E; Wall, Tamara L et al. (2016) The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans. Int J Mol Sci 17:
Yong, Weidong; Spence, John Paul; Eskay, Robert et al. (2014) Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats. Alcohol Clin Exp Res 38:1275-83
Spence, John Paul; Lai, Dongbing; Shekhar, Anantha et al. (2013) Quantitative trait locus for body weight identified on rat chromosome 4 in inbred alcohol-preferring and -nonpreferring rats: potential implications for neuropeptide Y and corticotrophin releasing hormone 2. Alcohol 47:63-7
Bice, Paula J; Liang, Tiebing; Zhang, Lili et al. (2010) Fine mapping and expression of candidate genes within the chromosome 10 QTL region of the high and low alcohol-drinking rats. Alcohol 44:477-85
Liang, Tiebing; Kimpel, Mark W; McClintick, Jeanette N et al. (2010) Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats. Genome Biol 11:R11
Alam, Imranul; Carr, Lucinda G; Liang, Tiebing et al. (2010) Identification of genes influencing skeletal phenotypes in congenic P/NP rats. J Bone Miner Res 25:1314-25
Alam, Imranul; Sun, Qiwei; Koller, Daniel L et al. (2010) Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats. Funct Integr Genomics 10:63-72
Spence, John P; Liang, Tiebing; Liu, Lixiang et al. (2009) From QTL to candidate gene: a genetic approach to alcoholism research. Curr Drug Abuse Rev 2:127-34
Alam, Imranul; Sun, Qiwei; Koller, Daniel L et al. (2009) Differentially expressed genes strongly correlated with femur strength in rats. Genomics 94:257-62

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