Activin in cerebral hypoxia and acute focal ischemia

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DESCRIPTION (provided by the applicant) Stroke is an enormous health challenge in the United States with over 700,000 people suffering from a brain attack every year with many of these individuals living with significant disabilities. Neurons respond to an ischemic stroke by activating signaling pathways and increasing gene expression. One approach for developing targeted stroke therapies is to identify the function of endogenous signals that increase following an ischemic insult. A second approach is to determine which genes are upregulated following nonlethal ischemic preconditioning, a mechanism that can partially alleviate neural damage if a preconditioning stimulus is given prior to a severe insult. The identification of the HIF-1 protein as a critical sensor of oxygen levels has lead to a greater understanding of the cellular and molecular sensing mechanisms involved in cerebral hypoxia and ischemia. Several HIF-1 target genes include growth factors which have been linked to neural protection against ischemic insult. This proposal tests the effect of HIF-1a stabilization on the growth factor activin and examines if activin actions promote neuronal survival in the setting of ischemic preconditioning. Preliminary results indicate that activin mRNA expression increases following hypoxia and acute ischemic injury and that added activin protects neuronal cells from oxidative stress in vitro. We hypothesize that HIF-1 activity results in increased activin expression and in addition, we propose that increased neural survival observed with ischemic preconditioning involves activin actions. Specific aim 1 tests if increases in HIF-1 activity in mice result in the induction of activin mRNA and smad2/3 activation. Specific aim 2 will examine the essential function of activin intracellular signaling in ischemic preconditioning in vitro. Specific aim 3 identifies which cell types synthesize activin and respond to its actions following a mouse model of focal cerebral ischemia. This proposal potentially identifies a novel HIF-1 target in cortical neurons and implicates activin and its signals in both ischemia and preconditioning effects.