Compulsive use of alcohol has been hypothesized to be driven by multiple sources of reinforcement that change with the individual's transition from social drinking to abuse and substance dependence on alcohol. The overarching hypothesis behind the present project is that understanding the dysregulations of the gene regulatory network that underlie the neuroadaptive changes associated with alcohol dependence will allow the identification of new and more effective therapeutic targets for alcohol abuse. Specifically, the goal of the present study is to use a state of the art systems biology strategy in conjunction with a validated rat model of dependence-induced escalated drinking and laser microdissection to reconstruct a Central Nervous System interactome (CNSi). The CNSi will integrate multiple levels of gene expression regulation including the transcriptional (mRNA), post-transcriptional (miRNA) and post-translational (protein-protein interactions and modulators of transcription factor activity) levels. The CNSi will be used to identify the master regulator genes (MRs) that activate specific gene signatures associated with the transition from moderate to excessive alcohol intake associated with dependence in brain regions of the reward and stress systems. The present multiple principal investigator (MPI) project will involve 2 components: 1) The Scripps Research Institute (TSRI) component will carry out the animal models and laser microdissections of brain regions relevant to the reward and stress systems;2) the Columbia University (CU) component will execute the systems biology strategy. It is expected that the identification of MRs of excessive alcohol intake and modulators of their activity will inform new therapeutic strategies and candidate druggable targets.

Public Health Relevance

The proposed study is aimed at dissecting molecular interactions involved in the transition from social drinking to excessive drinking and substance dependence on alcohol using a recently introduced systems biology strategy in conjunction with RNA-Seq, laser microdissections, and an established rat model of dependence-induced excessive drinking. The present computational-experimental approach will highlight the gene signatures associated with excessive drinking and the master regulator genes that regulate their expression. The results of the study will highlight new pathogenic mechanisms and therapeutic strategies for treatment and prevention of alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
3R01AA021667-02S2
Application #
8927137
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02))
Program Officer
Reilly, Matthew
Project Start
2013-09-05
Project End
2018-08-31
Budget Start
2014-09-15
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
$240,000
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Repunte-Canonigo, Vez; Lefebvre, Celine; George, Olivier et al. (2014) Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats. Mol Neurodegener 9:26