The goal of this project is to study the function of four genes in rodent models of binge drinking and ethanol dependence. The genes include Lmo3 and Lmo4, which encode transcriptional regulators, Alk, which encodes a receptor tyrosine kinase, and Mdk, which encodes a ligand that regulates the Alk gene product. Preliminary work in the investigator's laboratory and in the laboratories of other members of the INIA-West consortium suggests that these four genes cooperate to regulate behaviors associated with excessive alcohol consumption. The proposed work includes four types of experiments: (1) behavioral studies in genetically engineered mice to critically test the role of these four genes in alcohol-related behaviors, (2) experiments to map the brain regions where these genes function, (3) experiments to determine if alcohol affects the expression and function of these genes, and (4) experiments to identify downstream pathways by which these genes exert their effects. The work will provide basic insights into the role of a new signaling pathway in controlling behaviors that model human alcohol abuse. In addition, some of the genes in the pathway are protein kinases, which are regarded as excellent targets for drug development. Successful accomplishment of the project will thus lay the groundwork for development of totally novel, and much needed, pharmacotherapies for alcohol abuse in humans.

Public Health Relevance

Alcohol use disorders place a tremendous burden on individuals and society. The few available treatments have only limited efficacy. The proposed work will advance our basic understanding of a novel pathway that regulates behaviors associated with excessive drinking and identify targets for the development of much needed therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA020912-04
Application #
8604204
Study Section
Special Emphasis Panel (ZAA1-DD (50))
Program Officer
Reilly, Matthew
Project Start
2011-09-05
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$244,912
Indirect Cost
$91,186
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Dutton 3rd, John W; Chen, Hu; You, Chang et al. (2016) Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area. Addict Biol :
Lasek, Amy W (2016) Effects of Ethanol on Brain Extracellular Matrix: Implications for Alcohol Use Disorder. Alcohol Clin Exp Res 40:2030-2042
Schweitzer, Paul; Cates-Gatto, Chelsea; Varodayan, Florence P et al. (2016) Dependence-induced ethanol drinking and GABA neurotransmission are altered in Alk deficient mice. Neuropharmacology 107:1-8
He, Donghong; Chen, Hu; Muramatsu, Hisako et al. (2015) Ethanol activates midkine and anaplastic lymphoma kinase signaling in neuroblastoma cells and in the brain. J Neurochem 135:508-21
Chen, Hu; He, Donghong; Lasek, Amy W (2015) Repeated Binge Drinking Increases Perineuronal Nets in the Insular Cortex. Alcohol Clin Exp Res 39:1930-8
Savarese, A; Zou, M E; Kharazia, V et al. (2014) Increased behavioral responses to ethanol in Lmo3 knockout mice. Genes Brain Behav 13:777-83
Maiya, Rajani; Kharazia, Viktor; Lasek, Amy W et al. (2012) Lmo4 in the basolateral complex of the amygdala modulates fear learning. PLoS One 7:e34559