The Woriey project examines molecular mechanisms of activity-dependent synaptic plasticity that contribute to drug addiction.
Aim 1 will use newly developed mouse models that afford in vivo regulation of expression of the immediate eariy gene (IEG) Rhebl to examine how signaling of the mammalian target of rapamycin (mTOR) controls dynamic protein translation. In work supported by this grant, we have demonstrated that Rhebl is essential and sufficient to activate mTORCI in vivo, and have established viable mouse models that either conditionally delete Rhebl or express an activated Rhebl transgene (Zou et al., 2011). To explore the role of mTOR in protein translation, we will process brains of Rhebl transgenic mice to isolate mRNAs that are associated with polyribosomes or ribosomes in the process of translation initiation, and identify those RNA sequences that are protected from RNase digestion using RNA seq (Ingolia et al., 2009). Studies will test the hypothesis that mTOR controls translation of a specific set of brain mRNAs, and will test the "scanning" hypothesis for translation initiation.
Aim 2 will focus on mTOR-dependent proteins that are generated in neurons, and that regulate myelination in the CNS. Myelination is known to be dependent on neural activity and is disrupted in patients with drug addiction, however the molecular basis ofthis process is unknown. Rhebl transgenic mice show prominent changes in myelination (Zou et al., 2011) and preliminary studies indicate a role for neuron-generated proteins that control the differentiation of oligodendrites and their generation of myelin proteins. Information from Aim 1 mRNA analysis and direct assays of protein expression will generate candidate proteins, and these will be tested using in vivo assays for effects on myelination.
Aim 3 will explore the role of a novel protein family termed LanCLI in regulation of activity- dependent reactive oxygen species (ROS). LanCLI is regulated as an lEG and is highly expressed in normal brain. We have developed models that conditionally delete LanCLI gene or express LanCLI transgene in brain and we will use these models to test the hypothesis that dynamic expression of LanCLI is essential for normal synaptic plasticity and cocaine-evoked plasticity.

Public Health Relevance

The Woriey project examines biochemical signalling pathways that control brain metabolism to assess how they contribute to drug addiction. These signalling pathways play an important role in brain plasticity and influence mRNA translation, the generation of myelin, and the response to oxidative stress. Studies will contribute to a deep understanding of the molecular basis of neural plasticity and drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
2P50DA000266-41
Application #
8355366
Study Section
Special Emphasis Panel (ZDA1-EXL-T (02))
Project Start
Project End
Budget Start
2012-07-15
Budget End
2013-05-31
Support Year
41
Fiscal Year
2012
Total Cost
$358,440
Indirect Cost
$137,181
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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