This proposal investigates the implication of both genetic variation and epigenetic modification on HPA axis regulation and excessive alcohol consumption in primates. These studies will draw upon the rhesus macaque ethanol self-administration model, which will enable a longitudinal study design examining genomic DNA methylation before and after 12 months of ethanol consumption, accurate measure of ethanol intake and endocrine levels, and access to both blood and brain tissue samples for the comparison of epigenetic changes in both tissues. We will use whole-genome approaches to measure CpG methylation levels in the tissues before and after chronic ethanol consumption. We will test whether changes in methylation levels are associated with corresponding changes in gene expression. We will also test whether changes in methylation patterns in the blood parallel those found in the brain. Also taking advantage of the high efficiency of next generation sequencing technology, we will sequence neurotransmitter genes from the HPA axis and monoamine signaling pathways in a large cohort of animals. We will test the association between common variants and endocrine dysfunction, and will evaluate potential additive effects and interactions between risk alleles in multiple signaling pathways. We will also explore whether there is an association between specific alleles or haplotypes and changes in methylation following chronic alcohol consumption (allele-specific methylation). Together, these approaches will provide a comprehensive basis for evaluating the cumulative genetic vulnerabilities that contribute to excessive alcohol use. Owing to the close evolutionary relationship of non-human primates, these studies will have a high-degree of translational relevance to human alcoholism, potentially 1) identifying alcohol-linked epigenetic modification of genes, 2) determining the relevance of epigenetic modifications in a clinically accessible tissue (blood) to those in the brain and 3) suggesting novel targets for the future treatment of alcohol use disorders.

Public Health Relevance

This study will investigate the effect of chronic alcohol use on DNA and gene expression. These studies will determine whether DNA modifications are detected in the blood and brain, and if the changes in the two tissues are similar. These studies represent a novel approach to understanding the epigenetic consequences of alcohol use, and could indicate new directions for the treatment of alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA020928-04
Application #
8797291
Study Section
Special Emphasis Panel (ZAA1-DD (51))
Program Officer
Reilly, Matthew
Project Start
2012-02-15
Project End
2017-01-13
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
4
Fiscal Year
2015
Total Cost
$246,986
Indirect Cost
$105,851
Name
Oregon Health and Science University
Department
Genetics
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Tang, Gui-Hua; Dong, Zhen; Guo, Yan-Qiong et al. (2017) Psiguajadials A-K: Unusual Psidium Meroterpenoids as Phosphodiesterase-4 Inhibitors from the Leaves of Psidium guajava. Sci Rep 7:1047
Cervera-Juanes, R; Wilhelm, L J; Park, B et al. (2017) Alcohol-dose-dependent DNA methylation and expression in the nucleus accumbens identifies coordinated regulation of synaptic genes. Transl Psychiatry 7:e994
Cervera-Juanes, Rita; Wilhelm, Larry J; Park, Byung et al. (2017) Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking. Alcohol 60:103-113
Cervera-Juanes, R; Wilhem, L J; Park, B et al. (2016) MAOA expression predicts vulnerability for alcohol use. Mol Psychiatry 21:472-9
Liu, Xin; Zhang, Junsheng; Liu, Qiao et al. (2015) Bioactive cembranoids from the South China Sea soft coral Sarcophyton elegans. Molecules 20:13324-35
Ferguson, B; Hunter, J E; Luty, J et al. (2012) Genetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation in macaques. Genes Brain Behav 11:949-57