Stroke is a leading cause of death and disability in the United States, for which effective treatments remain elusive. Astrocyte survival is likely an important determinant of stroke volume and neuronal survival as loss of astrocyte viability would be predicted to augment stroke damage by glutamate release, collateral damage, and loss of their neuronal supportive functions. Thus, dissecting the molecular mechanisms by which astrocyte viability is altered during stroke would be an important advance. A principal mechanism by which astrocytes adapt to the hypoxic environment during stroke through the actions of hypoxia inducible factor 1 alpha (HIF-1a). HIF-1a, the master regulator of the cellular response to hypoxia, is a transcription factor stabilized and activated during hypoxia. HIF-1a markedly increases the expression of multiple genes including those that would be predicted to improve survival and ones that would have a pro-apoptotic function. The conditions that control the pro-survival or pro-apoptotic functions of HIF-1a remain undefined. Preliminary data suggests that HIF-1apro- apoptotic functions predominate in astrocytes during severe hypoxic stress enhancing cell death. The molecular mechanisms by which HIF-1cc induces cell death is unknown but may involve induction of pro-apoptotic members of the Bcl2 family Nip3, Nix, or Noxa. Furthermore, by associating with thepro- apoptotic transcription factor p53, HIF-1a may increase the pro-apoptotic functions of p53 during severe hypoxic stress. In contrast, pro-survival functions may be selectively induced during mild hypoxia. In fact, several reports suggest that HIF-1a plays a prominent role in the neuroprotection afforded by the mild hypoxic stimulus of hypoxic preconditioning (HPC). Furthermore, hypoxia mimetic (HM) compounds, which induce HIF-1a protein and transactivation of HIF-1a target genes, are neuroprotective when used as a preconditioning stimulus and are actively being pursued as stroke therapeutics. This proposal will evaluate the role of HIF-1a in mediating pro-survival or pro-death functions in astrocytes during stroke, following HPC, and with administration of HM compounds. We postulate that HIF-1a function in astrocytes contributes to astrocyte cell death during the severe hypoxia and ischemia present during stroke. In contrast, we predict that during the mild hypoxic stress of hypoxic preconditioning, HIF-1a function in astrocytes mediates improved astrocyte and neuronal viability. Using in vitro and in vivo methodology, we will examine these postulates.
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