Dysregulation of cellular Zn2+ has been tightly linked to neuronal injury in neurodegenerative conditions present in stroke, trauma and epilepsy. Our group first suggested that Zn2+ released from intracellular binding proteins by oxidative and nitrosative stress represents a critical and ubiquitous component in the activation of neuronal cell death processes in these and other neurological disorders. In work performed during the first funding period of this grant, we characterized cell death signaling cascades accompanied by intracellular Zn2+ liberation, and demonstrated in vivo injurious intraneuronal accumulation of this metal in the absence of synaptic Zn2+ release. The completion and publication of nearly all of the originally proposed experiments has allowed us to continue to expand our work in this novel and exciting area of research. In this competitive renewal application we propose: 1) To establish the mechanism by which intracellular Zn2+ release activates specific MAPK-dependent cell death signaling pathways. With these studies, we aim to eventually characterize the process by which Zn2+ can initiate divergent signaling processes. 2) To investigate the factors that modulate Zn2+-regulated neuronal gene expression in order to resolve conditions affecting Zn2+ buffering systems and, ultimately, Zn2+ cellular homeostasis. These studies aim to elucidate the fundamental properties of Zn2+-mediated gene expression in neurons, a relatively unexplored but critically important area of research. And 3) to determine the molecular cell-death pathway activated by intracellular Zn2+ release in vivo and uncover the endogenous stimulus for the liberation of this metal. Our long-term objectives are to characterize in detail the molecular signaling cascades leading to neuronal cell death following the liberation of intracellular Zn2+. As such, results of these studies will likely generate new avenues for therapeutic intervention in the large number of neurodegenerative disorders associated with oxidative and nitrosative injury.

Public Health Relevance

Results from these studies will provide fundamental information about the cellular mechanisms responsible for a host of neurological disorders, including stroke, trauma and epilepsy. With this information, we hope to uncover novel therapeutic strategies to prevent or halt the progression of these and other neurodegenerative conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043277-10
Application #
8206868
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Gubitz, Amelie
Project Start
2002-04-01
Project End
2013-09-14
Budget Start
2012-01-01
Budget End
2013-09-14
Support Year
10
Fiscal Year
2012
Total Cost
$324,778
Indirect Cost
$110,403
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Schulien, Anthony J; Justice, Jason A; Di Maio, Roberto et al. (2016) Zn(2+) -induced Ca(2+) release via ryanodine receptors triggers calcineurin-dependent redistribution of cortical neuronal Kv2.1 K(+) channels. J Physiol 594:2647-59
Li, Dong; Yuan, Hongjie; Ortiz-Gonzalez, Xilma R et al. (2016) GRIN2D Recurrent De Novo Dominant Mutation Causes a Severe Epileptic Encephalopathy Treatable with NMDA Receptor Channel Blockers. Am J Hum Genet 99:802-816
Aizenman, Elias; Mastroberardino, Pier G (2015) Metals and neurodegeneration. Neurobiol Dis 81:1-3
Hershfinkel, Michal; Ford, Dianne; Kelleher, Shannon et al. (2015) Seashells by the zinc shore: a meeting report of the International Society for Zinc Biology, Asilomar, CA 2014. Metallomics 7:1299-304
Gilad, David; Shorer, Sharon; Ketzef, Maya et al. (2015) Homeostatic regulation of KCC2 activity by the zinc receptor mZnR/GPR39 during seizures. Neurobiol Dis 81:4-13
Clemens, Katerina; Yeh, Chung-Yang; Aizenman, Elias (2015) Critical role of Casein kinase 2 in hepatitis C NS5A-mediated inhibition of Kv2.1 K(+) channel function. Neurosci Lett 609:48-52
Shah, Niyathi H; Schulien, Anthony J; Clemens, Katerina et al. (2014) Cyclin e1 regulates Kv2.1 channel phosphorylation and localization in neuronal ischemia. J Neurosci 34:4326-31
McCord, Meghan C; Kullmann, Paul H; He, Kai et al. (2014) Syntaxin-binding domain of Kv2.1 is essential for the expression of apoptotic K+ currents. J Physiol 592:3511-21
Shah, Niyathi Hegde; Aizenman, Elias (2014) Voltage-gated potassium channels at the crossroads of neuronal function, ischemic tolerance, and neurodegeneration. Transl Stroke Res 5:38-58
McCord, Meghan C; Aizenman, Elias (2014) The role of intracellular zinc release in aging, oxidative stress, and Alzheimer's disease. Front Aging Neurosci 6:77

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