Activin in cerebral hypoxia and acute focal ischemia

描述（由申请人提供） 中风在美国是一个巨大的健康挑战，有超过70万人患有中风。 每年都有脑梗死，其中许多人患有严重残疾。神经元通过激活信号通路和增加基因表达对缺血性中风作出反应。开发靶向卒中治疗的一种方法是鉴定缺血性损伤后增加的内源性信号的功能。第二种方法是确定哪些基因在非致死性缺血预处理后上调，如果在严重损伤之前给予预处理刺激，这种机制可以部分减轻神经损伤。HIF-1蛋白作为氧水平的关键传感器的鉴定导致了对脑缺氧和缺血中涉及的细胞和分子传感机制的更深入理解。几个HIF-1靶基因包括生长因子，其与神经保护对抗缺血性损伤有关。该提议测试了HIF-1a稳定化对生长因子激活素的影响，并检查了在缺血预处理的情况下激活素的作用是否促进神经元存活。初步结果表明，激活素的mRNA表达增加后，缺氧和急性缺血性损伤，并增加激活素保护神经元细胞在体外氧化应激。我们假设HIF-1活性导致激活素表达增加，此外，我们提出缺血预处理观察到的神经存活增加涉及激活素作用。特定目标1测试小鼠中HIF-1活性的增加是否导致激活素mRNA的诱导和smad 2/3激活。具体目标2将在体外研究激活素细胞内信号转导在缺血预适应中的重要作用。具体目标3确定哪些细胞类型合成激活素并在小鼠局灶性脑缺血模型后对其作用作出反应。这一建议可能确定了一个新的HIF-1靶在皮层神经元和牵连激活素及其信号在缺血和预处理的影响。

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.