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

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZDA1-EXL-T (02))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
United States
Zip Code
Scarffe, Leslie A; Stevens, Daniel A; Dawson, Valina L et al. (2014) Parkin and PINK1: much more than mitophagy. Trends Neurosci 37:315-24
Andrabi, Shaida A; Umanah, George K E; Chang, Calvin et al. (2014) Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis. Proc Natl Acad Sci U S A 111:10209-14
Selvakumar, Balakrishnan; Campbell, Peter W; Milovanovic, Mike et al. (2014) AMPA receptor upregulation in the nucleus accumbens shell of cocaine-sensitized rats depends upon S-nitrosylation of stargazin. Neuropharmacology 77:28-38
Chen, Yu-Chan; Umanah, George K E; Dephoure, Noah et al. (2014) Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins. EMBO J 33:1548-64
Prendergast, Jillian; Umanah, George K E; Yoo, Seung-Wan et al. (2014) Ganglioside regulation of AMPA receptor trafficking. J Neurosci 34:13246-58
Rao, Feng; Xu, Jing; Khan, A Basit et al. (2014) Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNA repair and cell death. Proc Natl Acad Sci U S A 111:16005-10
Huang, Chao; Chen, Mina; Pang, Dejiang et al. (2014) Developmental and activity-dependent expression of LanCL1 confers antioxidant activity required for neuronal survival. Dev Cell 30:479-87
Lee, Yun-Il; Giovinazzo, Daniel; Kang, Ho Chul et al. (2014) Protein microarray characterization of the S-nitrosoproteome. Mol Cell Proteomics 13:63-72
Fatokun, Amos A; Dawson, Valina L; Dawson, Ted M (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol 171:2000-16
Rao, Feng; Cha, Jiyoung; Xu, Jing et al. (2014) Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2. Mol Cell 54:119-32

Showing the most recent 10 out of 37 publications