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 trigger for 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 resulting from ntracellular 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 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. Relevance to public health. 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
High Priority, Short Term Project Award (R56)
Project #
2R56NS043277-06
Application #
7441308
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Golanov, Eugene V
Project Start
2002-04-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2009-07-31
Support Year
6
Fiscal Year
2007
Total Cost
$371,250
Indirect Cost
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Justice, Jason A; Schulien, Anthony J; He, Kai et al. (2017) Disruption of KV2.1 somato-dendritic clusters prevents the apoptogenic increase of potassium currents. Neuroscience 354:158-167
Yeh, Chung-Yang; Bulas, Ashlyn M; Moutal, Aubin et al. (2017) Targeting a Potassium Channel/Syntaxin Interaction Ameliorates Cell Death in Ischemic Stroke. J Neurosci 37:5648-5658
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
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
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
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 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
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 (2013) Convergent Ca2+ and Zn2+ signaling regulates apoptotic Kv2.1 K+ currents. Proc Natl Acad Sci U S A 110:13988-93
Perez-Rosello, Tamara; Anderson, Charles T; Schopfer, Francisco J et al. (2013) Synaptic Zn2+ inhibits neurotransmitter release by promoting endocannabinoid synthesis. J Neurosci 33:9259-72

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