Exposure to drugs of abuse results in changes in gene expression, chromatin remodeling, cell signaling, and neuronal plasticity that leads to changes in behavior and with repetitive and increased exposure results in cell injury and cell death. To discover signaling pathways responsible for maintaining homeostatic processes to promote effective cell signaling and survival in a hostile setting we performed a series of genetic screens and discovered Iduna. The PAR binding and E3 ligase actions of Iduna are important for neuroprotection, DNA repair and cell viability following DNA damage. Iduna is induced by stress and expressed during periods of plasticity positioning Iduna to play key roles in regulating genetic and/or protein expression that mediate neuronal plasticity. To explore these diverse actions of Iduna with relevance to the stress of cocaine exposure we propose the following aims:
Specific Aim 1 : How does Iduna regulate cell survival? We will examine the Iduna proteome to identify and characterize a full complement of Iduna target proteins to better understand pathways to neuroprotection.
Specific Aim 2; What is the role of Iduna in activity dependent epigenetic modification and regulation? Histone modification and DNA methylation are key events in the complex behavioral responses to drugs of abuse, in particular to cocaine. In exploring Iduna biology we discovered that PAR is a major epigenetic regulator of gene expression. How PAR regulates gene transcription and protein translation is yet to be discovered.
Specific Aim 3 : Identification and characterization of the Iduna in the regulation of microRNA processing. PAR signaling is important in the formation of cytoplasmic stress granules and thus control protein translation by altering microRNA stability. PAR modification of stress granule proteins results in silencing of microRNA. Iduna is localized to stress granules. Its function in regulating expression of stress granule proteins and thus the stability of microRNA will be explored. Through these innovative aims exploring new biology with advanced technology we will provide new information regarding the role of Iduna in neuronal viability, epigenetic regulation and microRNA stability in the stress response to the drug of abuse, cocaine.

Public Health Relevance

Exposure to the drug of abuse, cocaine, initiates a complex choreography of detrimental cell signaling. Iduna is induced in response to this stress in a response to maintain homeostasis, efficient cell function and cell viability. Understanding the complex events regulated by Iduna will lead to new knowledge regarding the long lasting changes in cell function that underiie the behavioral response to drugs of abuse and may in the future direct new treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA000266-43
Application #
8663846
Study Section
Special Emphasis Panel (ZDA1-EXL-T)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
43
Fiscal Year
2014
Total Cost
$415,386
Indirect Cost
$158,975
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Harraz, Maged M; Snyder, Solomon H (2017) Antidepressant Actions of Ketamine Mediated by the Mechanistic Target of Rapamycin, Nitric Oxide, and Rheb. Neurotherapeutics 14:728-733
Park, Alan Jung; Havekes, Robbert; Fu, Xiuping et al. (2017) Learning induces the translin/trax RNase complex to express activin receptors for persistent memory. Elife 6:
Fu, Chenglai; Xu, Jing; Cheng, Weiwei et al. (2017) Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via ?-actinin and focal adhesion kinase. Proc Natl Acad Sci U S A 114:2036-2041
Paul, Bindu D; Snyder, Solomon H (2017) Gasotransmitter hydrogen sulfide signaling in neuronal health and disease. Biochem Pharmacol :
Dawson, Ted M; Dawson, Valina L (2017) Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics. Annu Rev Pharmacol Toxicol 57:437-454
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 133:225-232
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
Rosenthal, Liana S; Drake, Daniel; Alcalay, Roy N et al. (2016) The NINDS Parkinson's disease biomarkers program. Mov Disord 31:915-23
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
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

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