Recent studies have demonstrated that microRNA (miRNA) signaling pathways play a prominent role in regulating behavioral responses to cocaine. Therefore, studies aimed at understanding how the miRNA system operates are directly relevant to drug abuse research. Recent studies also indicate that the translin/trax RNAse complex plays a key role in miRNA processing. Furthermore, we have found, in preliminary studies, that translin knockout mice display reduced locomotor responses to cocaine. Accordingly, we plan to define: 1) the role of the translin/trax complex in regulating miRNA processing, and 2) its role in regulating responsiveness to cocaine. Accordingly, the specific aims of the proposed project are to: I. Identify direct miRNA targets of the translin/trax RNAse complex and determine its role in their processing. Although the translin/trax complex has been implicated in processing miRNAs, it is still unclear which specific miRNAs it targets directly. Accordingly, we plan to use a highly efficient UV-crosslinking procedure (PAR- CLIP) to identify RNAs that bind directly to the translin/trax complex in intact cells. II. Determine the impact of translin deletion on signaling pathways that regulate responsiveness to cocaine. As translin and trax are expressed in striatal neurons, a major site of cocaine action, we plan, in this set of studies, to conduct both candidate-based and screening approaches to identify alterations in striatal signaling pathways caused by translin deletion. III. Determine whether deletion of translin from striatal neurons mediates altered responsiveness to cocaine. Our initial studies demonstrating that translin deletion impairs the locomotor response to cocaine were performed in conventional ko mice. Accordingly, we plan, in this set of studies, to generate and use translin conditional ko mice to test the hypothesis that deletion of translin from D1R- and/or D2R-positive neurons mediates this behavioral phenotype.

Public Health Relevance

To help develop improved approaches to prevent and treat drug abuse, a major goal of research in this field is to define the neurobiological changes that mediate the reinforcing properties of drugs of abuse. Recent studies have revealed that a newly identified class of RNA molecules, called microRNAs, play a key role in regulating behavioral responses to drugs of abuse. Accordingly, the goal of this proposal is to understand the role of the translin/trax comnlex in regulating microRNA nrocessina and behavioral responses to cocaine

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA000266-42
Application #
8509654
Study Section
Special Emphasis Panel (ZDA1-EXL-T)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
42
Fiscal Year
2013
Total Cost
$208,300
Indirect Cost
$79,719
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102
Davis, Marie Y; Johnson, Catherine O; Leverenz, James B et al. (2016) Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 73:1217-1224
Cozzoli, Debra K; Courson, Justin; Rostock, Charlotte et al. (2016) Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption. Biol Psychiatry 79:443-51
Harraz, M M; Tyagi, R; Cortés, P et al. (2016) Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry 21:313-9
Guha, Prasun; Harraz, Maged M; Snyder, Solomon H (2016) Cocaine elicits autophagic cytotoxicity via a nitric oxide-GAPDH signaling cascade. Proc Natl Acad Sci U S A 113:1417-22
Scherer, Paul C; Ding, Yan; Liu, Zhiqing et al. (2016) Inositol hexakisphosphate (IP6) generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. Proc Natl Acad Sci U S A 113:3503-8
Fu, Xiuping; Shah, Aparna; Baraban, Jay M (2016) Rapid reversal of translational silencing: Emerging role of microRNA degradation pathways in neuronal plasticity. Neurobiol Learn Mem 133:225-32
Xu, Jin-Chong; Fan, Jing; Wang, Xueqing et al. (2016) Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity. Sci Transl Med 8:333ra48
Mills, Kelly A; Mari, Zoltan; Bakker, Catherine et al. (2016) Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. Parkinsonism Relat Disord 33:102-106
Rao, Feng; Xu, Jing; Fu, Chenglai et al. (2015) Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1. Proc Natl Acad Sci U S A 112:1773-8

Showing the most recent 10 out of 83 publications