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 #
3U01AA020912-06S1
Application #
9324480
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Reilly, Matthew
Project Start
2011-09-05
Project End
2017-01-31
Budget Start
2016-09-01
Budget End
2017-01-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Fernández-Calle, Rosalía; Vicente-Rodríguez, Marta; Pastor, Miryam et al. (2018) Pharmacological inhibition of Receptor Protein Tyrosine Phosphatase ?/? (PTPRZ1) modulates behavioral responses to ethanol. Neuropharmacology 137:86-95
Pastor, Miryam; Fernández-Calle, Rosalía; Di Geronimo, Bruno et al. (2018) Development of inhibitors of receptor protein tyrosine phosphatase ?/? (PTPRZ1) as candidates for CNS disorders. Eur J Med Chem 144:318-329
Satta, Rosalba; Hilderbrand, Elisa R; Lasek, Amy W (2018) Ovarian Hormones Contribute to High Levels of Binge-Like Drinking by Female Mice. Alcohol Clin Exp Res 42:286-294
Savarese, Antonia; Lasek, Amy W (2018) Regulation of anxiety-like behavior and Crhr1 expression in the basolateral amygdala by LMO3. Psychoneuroendocrinology 92:13-20
Hilderbrand, Elisa R; Lasek, Amy W (2018) Studying Sex Differences in Animal Models of Addiction: An Emphasis on Alcohol-Related Behaviors. ACS Chem Neurosci 9:1907-1916
Savarese, Antonia M; Lasek, Amy W (2018) Transcriptional Regulators as Targets for Alcohol Pharmacotherapies. Handb Exp Pharmacol 248:505-533
Hilderbrand, Elisa R; Lasek, Amy W (2018) Estradiol enhances ethanol reward in female mice through activation of ER? and ER?. Horm Behav 98:159-164
Lasek, Amy W; Chen, Hu; Chen, Wei-Yang (2018) Releasing Addiction Memories Trapped in Perineuronal Nets. Trends Genet 34:197-208
Dutton 3rd, John W; Chen, Hu; You, Chang et al. (2017) Anaplastic lymphoma kinase regulates binge-like drinking and dopamine receptor sensitivity in the ventral tegmental area. Addict Biol 22:665-678
Vandegrift, Bertha J; You, Chang; Satta, Rosalba et al. (2017) Estradiol increases the sensitivity of ventral tegmental area dopamine neurons to dopamine and ethanol. PLoS One 12:e0187698

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