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

基本信息

批准号：
7677913
负责人：
Shibani Sharon Mukerji
金额：
$ 2.74万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
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/7677913
关键词：
Activins Acute Antibodies Astrocytes Biological Assay Brain Brain Hypoxia-Ischemia Cell Survival Cells Cerebral Hypoxia Cerebral Ischemia Cerebral Ischemia-Hypoxia Cerebrum 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

项目摘要

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）中风在美国是一项巨大的健康挑战，有超过 700,000 人患有中风每年都有脑部发作，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来应对缺血性中风。开发靶向中风疗法的一种方法是识别缺血性损伤后增加的内源信号的功能。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使人们对脑缺氧和缺血所涉及的细胞和分子传感机制有了更深入的了解。一些 HIF-1 靶基因包括生长因子，这些因子与针对缺血性损伤的神经保护有关。该提案测试了 HIF-1a 稳定性对生长因子激活素的影响，并检查激活素的作用是否可以在缺血预处理的情况下促进神经元存活。初步结果表明，缺氧和急性缺血性损伤后激活素 mRNA 表达增加，并且添加的激活素可在体外保护神经元细胞免受氧化应激。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的作用。具体目标 1 测试小鼠中 HIF-1 活性的增加是否会导致激活素 mRNA 和 smad2/3 激活的诱导。具体目标 2 将检查激活素细胞内信号传导在体外缺血预处理中的基本功能。具体目标 3 确定哪些细胞类型合成激活素并对其在局灶性脑缺血小鼠模型中的作用做出反应。该提议有可能确定皮质神经元中的一个新的 HIF-1 靶点，并暗示激活素及其信号在缺血和预处理作用中的作用。