In the stroke penumbra, astrocyte function may support or impede neuronal survival depending on the relative contributions of their adaptive and pathological functions. This proposal will examine putative pathological roles of the transcription factor hypoxia inducible factor 1alpha (HIF-la) in astrocytes during stroke. HIF-la, the master regulator of the cellular response to hypoxia, is a transcription factor stabilized and activated during hypoxia. HIF-la markedly increases the expression of numerous transcripts including gene products that would be predicted to improve survival and those that are pro-apoptotic. The conditions under which these divergent targets are evoked are undefined but may related to the degree of hypoxic stress the cells experience. Prolyl hydroxylase inhibitors, which induce HIF-la protein and transactivation of HIF-la targets, are protective in animal stroke models. Furthermore, studies suggest that HIF-1a function may play a role in the protection mediated by hypoxic preconditioning. Thus, compounds that activate HIF- la function are actively being pursued as stroke therapeutics. Yet, under conditions of severe ischemia, HIF- la also clearly has pathological functions. For example, a dominant negative form of HIF-la attenuates neuronal death during oxygen glucose deprivation. Utilizing mice with a conditional loss of HIF-1 a function, recent work by other investigators support a pro-apoptotic role for HIF-1a in neurons following transient global ischemia. The mechanism(s) by which HIF-la induced neuronal death in these studies remains speculative, but several pro-apoptotic targets of HIF-la are described. Moreover, HIF-1a dependent stabilization of p53 may contribute to its pro-death phenotype. Yet, the function of HIF-1a within astrocytes during ischemia remains largely unexplored. Similar to that described for neurons, we have preliminary data that suggests HIF-la has a pathological role in astrocytes. Wepostulate that HIF-la function in astrocytes contributes to astrocyte and neuronal cell death during the severe hypoxia and ischemia present during stroke. Utilizing in vitro and in vivo models, we will examine the role of HIF-1a in determining astrocyte viability during ischemic conditions, the conditions that may differentially regulate adaptive or pathological HIF-1a targets in astrocytes, and the role of HIF-1a in astrocytes on neuronal survival during stroke.
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