Much attention has been paid to the possibility that excessive calcium influx may contribute to neuronal death after hypoxic-ischemic insults. Project I will turn a spotlight on an alternative divalent cation messenger mediating hypoxic-ischemic neuronal death, zinc. The hypothesis will be tested that the toxic translocation of synaptic Zn 2+ from presynaptic terminals into vulnerable postsynaptic neurons contributes to their demise after ischemic insults.
Three Aims are proposed.
The first Aim will set up a slice model of oxygen-glucose deprivation-induced, Zn 2+ mediated neuronal death where changes in neuronal intracellular free Zn 2+ ([Zn 2+]i) can be followed.
The second Aim will harness this model and see if several pharmacological, dietary, and genetic manipulations affecting the synaptic Zn 2+ system produce corresponding alterations in neuronal [Zn 2+ and neuronal death after oxygen-glucose deprivation.
The third Aim will harness perspectives developed from in vitro experiments, and determine the extent to which toxic Zn 2+ influx contributes to neuronal death after transient global ischemia or mild focal ischemia in rats. Experiments in Project I should lead to an enhanced understanding of the newly identified contribution of Zn 2+ toxicity to hypoxic-ischemic brain damage, and thus aid the future development of effective clinical therapies or stroke and cardiac arrest.
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