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 #
5P50DA000266-42
Application #
8509652
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
$344,102
Indirect Cost
$131,694
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

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