This is a revised submission to request support for fimds to support continuation of a productive Program Project aimed in the long-term at understanding how cell-cell interactions influence the pathogencsis of hypoxic-ischemic brain injury. The current grant period focused on alpha- amino-3-hydroxy-5-methyl-4-isoxazolcpropionate (AMPA) / kainate receptor-mediated injury, whereas the present proposal follows up on several newer themes that emerged during the current period (2/02/95 - 1/31/00, P01 NS32636). The proposed experiments enlist the efforts of 10 faculty investigators, collaborating on 3 interlinked experimental Projects and 4 supporting Cores. Project 1 will test the hypothesis that toxic levels of Zn2+ entry may contribute to neuronal death after transient global ischemia and mild transient focal ischemia, utilizing both in vitro and in vivo injury models. Project II and III move past the main second messenger of injury, entry of Ca2+ or Zn2+, to examine later events. Project II will examine downstream intracellular processes, specifically examining hypoxia- induced changes in astrocyte mitochondrial free radical production, and testing a novel hypothesis that this increase in astrocyte free radial production contributes to neuronal death. Finally, Project III will look beyond the injury horizon and examine the recovery of dendritic structures and fimctional synapses post injury, specifically testing the hypothesis that synapses lost due to mild hypoxic insults can reform and regain firnction. These experimental sections are supported by an Administrative, Computing, and Statistics Core (A); an Animal Core (in vivo ischemia) (B); a Microscopy and Imaging Core (C); and a Stereology Core (D). Besides sharing a central investigative theme of cell-cell interactions, the three proposed Projects will collaborate on experiments involving specific signaling processes mediated by Zn2+ or astrocytes. Taken together, proposed experiments will combine molecular, cellular, and whole animal approaches to answer several specific questions relevant to understanding the pathogenesis of hypoxic-ischemic brain damage. Information gathered from these studies may aid the future development of effective clinical therapies for stroke and cardiac arrest.
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