This is an application for the NIDA sponsored K02 Independent Scientist Award. The long term goal of the candidate is to elucidate the mechanisms of G protein signaling regulation in the basal ganglia as a necessary prerequisite to understanding neurological diseases and addiction and developing means of their treatment. The main focus of the research proposal is on the central regulator of opioid and dopamine G protein signaling, RGS9-2 that has been implicated in addiction and drug abuse. We have recently discovered that RGS9-2 in the striatum exists in a complex with a novel neuronal protein which we named R7 Binding Protein (R7BP). The HYPOTHESIS addressed by this proposal is that R7BP serves as a critical regulator of RGS9-2 function in the striatal neurons by controlling the expression level, localization, and activity of RGS9-2. This hypothesis will be addressed in the following SPECIFIC AIMS: 1. to determine the mechanisms by which R7BP controls expression of RGS9-2 in striatal neurons. 2. To understand the role of R7BP in the regulation of RGS9-2 catalytic activity. 3. To further characterize the molecular composition of G protein inactivating complex in striatal neurons. In addition to pursuing the research goals, the applicant plans to undertake career development activities by: (I) establishing and/or maintaining active collaborations with leading researchers focusing on drug addiction mechanisms, (II) integrating my research program into the larger community efforts to understand mechanisms of drug addiction and (III) learning cutting edge behavioral and imaging approaches to study drug addiction and implanting them to pursue the research directions in the laboratory.

Public Health Relevance

The studies should provide an insight into the mechanisms that regulate reward processing in the basal ganglia of the brain. This knowledge will be important for better understanding of how drugs of abuse lead to addiction with the hopes for the future development of therapeutical intervention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA026405-06
Application #
8447523
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Hillery, Paul
Project Start
2009-04-01
Project End
2014-07-31
Budget Start
2013-04-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$121,500
Indirect Cost
$9,000
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
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Sarria, Ignacio; Orlandi, Cesare; McCall, Maureen A et al. (2016) Intermolecular Interaction between Anchoring Subunits Specify Subcellular Targeting and Function of RGS Proteins in Retina ON-Bipolar Neurons. J Neurosci 36:2915-25
Tayou, Junior; Wang, Qiang; Jang, Geeng-Fu et al. (2016) Regulator of G Protein Signaling 7 (RGS7) Can Exist in a Homo-oligomeric Form That Is Regulated by Gαo and R7-binding Protein. J Biol Chem 291:9133-47
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Xie, Keqiang; Colgan, Lesley A; Dao, Maria T et al. (2016) NF1 Is a Direct G Protein Effector Essential for Opioid Signaling to Ras in the Striatum. Curr Biol 26:2992-3003
Shamseldin, Hanan E; Masuho, Ikuo; Alenizi, Ahmed et al. (2016) GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition. Genome Biol 17:195
Victoria, Nicole C; Marron Fernandez de Velasco, Ezequiel; Ostrovskaya, Olga et al. (2016) G Protein-Gated K(+) Channel Ablation in Forebrain Pyramidal Neurons Selectively Impairs Fear Learning. Biol Psychiatry 80:796-806
Aguado, Carolina; Orlandi, Cesare; Fajardo-Serrano, Ana et al. (2016) Cellular and Subcellular Localization of the RGS7/Gβ5/R7BP Complex in the Cerebellar Cortex. Front Neuroanat 10:114
Orlandi, Cesare; Xie, Keqiang; Masuho, Ikuo et al. (2015) Orphan Receptor GPR158 Is an Allosteric Modulator of RGS7 Catalytic Activity with an Essential Role in Dictating Its Expression and Localization in the Brain. J Biol Chem 290:13622-39

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