Activin in cerebral hypoxia and acute focal ischemia

激活素在脑缺氧和急性局灶性缺血中的作用

• 批准号: 7275205
• 负责人: Shibani Sharon Mukerji
• 金额: $ 3.27万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275205
• 关键词: Activins; Acute; Antibodies; Astrocytes; Biological Assay; Brain; Brain Hypoxia-Ischemia; Cell Survival; Cells; Cerebral Hypoxia; Cerebral Ischemia; Cerebral Ischemia-Hypoxia; Cerebrum; Condition; Data; Development; Endothelial Cells; Equilibrium; Erythropoietin; Exposure to; Gene Expression; Gene Targeting; Genes; Glucose; Growth Factor; Health; Hour; Hypoxia; Immunochemistry; In Situ Hybridization; In Vitro; Individual; Infarction; Infection; Injury; Ischemia; Ischemic Preconditioning; Ischemic Stroke; Lead; Life; Link; Location; Mediating; Messenger RNA; Microglia; Molecular; Morbidity - disease rate; Mus; Neurons; Oxidative Stress; Oxygen; Pathway interactions; Pattern; Pharmaceutical Preparations; Proteins; Reaction; Role; Signal Pathway; Signal Transduction; Stimulus; Stroke; Testing; Time; United States; Vascular Endothelial Growth Factors; base; cell type; cytokine; deprivation; disability; hypoxia inducible factor 1; inhibitor/antagonist; intercellular communication; mRNA Expression; mortality; mouse model; neuronal survival; neutralizing antibody; novel; preconditioning; relating to nervous system; response; sensor; small molecule; stroke therapy; transcription factor

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.

描述(由申请人提供) 在美国，中风是一个巨大的健康挑战，超过70万人患有中风 每年，这些人中的许多人都患有严重的残疾。神经元通过激活信号通路和增加基因表达来应对缺血性中风。开发有针对性的中风治疗的一种方法是确定在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命性缺血预适应后上调，如果在严重侮辱之前给予预适应刺激，这种机制可以部分减轻神经损伤。HIF-1蛋白是氧水平的重要感受器，这一发现有助于我们更好地理解脑缺氧和脑缺血的细胞和分子传感机制。几个HIF-1靶基因包括生长因子，这些生长因子与防止缺血性损伤的神经保护有关。这项建议测试了HIF-1a稳定化对生长因子激活素的影响，并检查在缺血预适应的背景下，激活素的作用是否促进神经元存活。初步结果表明，在缺氧和急性缺血损伤后，激活素的mRNA表达增加，在体外添加激活素可以保护神经细胞免受氧化应激的影响。我们假设HIF-1活性导致激活素表达增加，此外，我们认为缺血预适应所观察到的神经元存活率增加与激活素作用有关。特定目的1测试小鼠HIF-1活性增加是否导致激活素mRNA和Smad2/3激活。特定目的2将在体外研究激活素细胞内信号在缺血预适应中的基本功能。特定目标3确定哪些细胞类型合成激活素，并在小鼠局部脑缺血模型后对其行为做出反应。这一建议潜在地确定了皮质神经元中的一个新的HIF-1靶点，并涉及到激活素及其信号在缺血和预适应效应中的作用。