Alcohol abuse disorders are a major health care concern that affect millions of people every year in the United States. Alcoholism has a significant genetic etiology, but few genes are known that significantly contribute to the development of the disease. The goal of this proposal is to study genes regulating the actin cytoskeleton, and the molecular mechanisms by which they do so, to regulate ethanol-induced behaviors in Drosophila. This idea emerged in parallel in two model organisms. First, previous genetic screens for Drosophila mutants with altered behavioral responses to alcohol identified mutations in multiple genes regulating the actin cytoskeleton. Second, mice with a knock-out of an actin regulatory protein also showed altered responses to alcohol, including increased voluntary drinking. We therefore postulate that the dynamic regulation of the actin cytoskeleton is a major determinant of behavioral responses to ethanol. We propose genetic, molecular, biochemical, and cell culture approaches to define the roles of two small GTPase pathways, the Arf6, and Rho-family of GTPases in regulating alcohol-induced behaviors. First, we will study how two distinct isoforms of a regulatory protein of Rho-GTPases, RhoGAP18B, are differentially involved in the regulation of both ethanol-induced hyperactivity, and sedation. Second, we will test mutations in members of the Arf6 signaling pathway for their responses to alcohol. Arf6 regulates membrane traffic and actin dynamics at the plasma membrane. We will use genetic, and biochemical approaches to define what the molecular links are between the Rho and Arf6 signaling pathways. Third, we will test the contribution of other actin regulatory genes to ethanol-induced behaviors, notably the role of cofilin, an actin-severing protein that controls the balance between free globular and filamentous actin protein. The members of these small GTPase signaling pathways are highly conserved from Drosophila to mammals, and some are known to participate in complex behaviors such as learning and memory, in vertebrates and invertebrates. We predict that these pathways are also functionally conserved in their regulation of ethanol-induced behaviors. Alcoholism is a devastating disease that severely impacts personal, and public health. The proposed research will advance our understanding of the genetic basis for the development of alcoholism. This in turn, will result in the identification of new risk factors and potential therapeutic targets for the treatment of alcohol abuse disorders.
Alcoholism is a devastating disorder that significantly contributes to mortality, disability, and to healthcare costs. The goal of this research is to understand the genes that determine, and mediate the behavioral responses to alcohol. In conducting this research, we hope to identify risk factors for the development of alcoholism, as well as provide leads for the development of new therapeutic strategies aiding in the treatment of alcohol use disorders.
| Gonzalez, D A; Jia, T; Pinzón, J H et al. (2018) The Arf6 activator Efa6/PSD3 confers regional specificity and modulates ethanol consumption in Drosophila and humans. Mol Psychiatry 23:621-628 |
| Shalaby, Nevine A; Pinzon, Jorge H; Narayanan, Anjana S et al. (2018) JmjC domain proteins modulate circadian behaviors and sleep in Drosophila. Sci Rep 8:815 |
| Kaun, Karla R; Rothenfluh, Adrian (2017) Dopaminergic rules of engagement for memory in Drosophila. Curr Opin Neurobiol 43:56-62 |
| Shalaby, Nevine A; Sayed, Raheel; Zhang, Qiao et al. (2017) Systematic discovery of genetic modulation by Jumonji histone demethylases in Drosophila. Sci Rep 7:5240 |
| Pinzón, Jorge H; Reed, Addison R; Shalaby, Nevine A et al. (2017) Alcohol-Induced Behaviors Require a Subset of Drosophila JmjC-Domain Histone Demethylases in the Nervous System. Alcohol Clin Exp Res 41:2015-2024 |
| Jia, Tianye; Macare, Christine; Desrivières, Sylvane et al. (2016) Neural basis of reward anticipation and its genetic determinants. Proc Natl Acad Sci U S A 113:3879-84 |
| Narayanan, Anjana S; Rothenfluh, Adrian (2016) I Believe I Can Fly!: Use of Drosophila as a Model Organism in Neuropsychopharmacology Research. Neuropsychopharmacology 41:1439-46 |
| Acevedo, Summer F; Peru y Colón de Portugal, Raniero L; Gonzalez, Dante A et al. (2015) S6 Kinase Reflects and Regulates Ethanol-Induced Sedation. J Neurosci 35:15396-402 |
| Ojelade, Shamsideen A; Acevedo, Summer F; Kalahasti, Geetha et al. (2015) RhoGAP18B Isoforms Act on Distinct Rho-Family GTPases and Regulate Behavioral Responses to Alcohol via Cofilin. PLoS One 10:e0137465 |
| Ojelade, Shamsideen A; Jia, Tianye; Rodan, Aylin R et al. (2015) Rsu1 regulates ethanol consumption in Drosophila and humans. Proc Natl Acad Sci U S A 112:E4085-93 |
Showing the most recent 10 out of 20 publications
