Sphingosine-1-phosphate-activated telomerase in stroke

1-磷酸鞘氨醇激活端粒酶在中风中的作用

• 批准号: 7140237
• 负责人: CHRISTIAN WAEBER
• 金额: $ 23.61万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-23 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140237
• 关键词: angiogenesis; apoptosis; cerebral ischemia /hypoxia; enzyme activity; genetically modified animals; glia; heat shock proteins; laboratory mouse; neurons; sphingosine; stroke; telomerase; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Stroke is a major cause of death and disability and brain blood vessels have been implicated. Stroke outcome is worsened by apoptotic death of endothelial cells (EC), failure of angiogenesis and insufficient growth of collateral vessels. In brain EC, sphingosine-1 -phosphate (S1P) activates Akt and telomerase, suppresses apoptosis and induces proliferation. Neurons, and possibly glial cells, are a source of S1P in ischemia because the S1P synthesizing enzyme (sphingosine kinase 2, SPK2) is upregulated in neurons following oxygen glucose deprivation and middle cerebral artery occlusion (MCAo) in mice. We hypothesize that following ischemia, neuron/glia-derived S1P exerts anti-apoptotic and pro-angiogenic effects on EC via telomerase. Two (2) specific aims will test the hypothesis that neuron/glia-derived S1P activates EC S1P1 receptors, Akt and telomerase, protecting EC from apoptosis and inducing neovascularization. Aim 1 (in vitro) will confirm and characterize the telomerase responses (activation and up-regulation) to S1P in EC, and test the hypothesis that S1P produced by neuronal and glial SPK2 induces telomerase activation, thereby mediating EC protection and proliferation. We propose that S1P1 receptors, Akt and Heat-Shock Protein 90 (HSP90) play a key role in these effects. Aim 2 (in vivo) will show that the S1P receptor agonist prodrug FTY720 increases telomerase expression in brain EC and extend preliminary findings showing that this agent decreases infarct size when administered before or after MCAo. Using transgenic mice expressing dominant negative Akt under the control of an EC-specific promoter, or mice lacking either the catalytic subunit or the RNA template of telomerase, we will test the hypothesis that the protective effect of FTY720 is related to Akt and telomerase activation in EC, and that this effect does not depend on the catalytic activity of telomerase (FTY720 should protect in RNA template knockouts).This project will study a novel system that can provide long-lasting improvement in EC function following stroke and serve as a new target for stroke therapy.

描述（由申请人提供）：中风是死亡和残疾和脑血管的主要原因。内皮细胞（EC）的凋亡死亡，血管生成的失败和副血管生长不足，中风的结果恶化了。在脑EC中，鞘氨醇1-磷酸（S1P）激活AKT和端粒酶，抑制凋亡并诱导增殖。神经元（可能是神经胶质细胞）是缺血中S1P的来源，因为在小鼠中，在氧气葡萄糖剥夺和中大脑动脉闭塞（MCAO）后，神经元中S1P合成酶（鞘氨醇激酶2，SPK2）在神经元中上调。我们假设以下缺血，神经元/胶质衍生的S1P对通过端粒酶对EC发挥抗凋亡和促血管生成作用。两（2）个特定目的将检验以下假设：神经元/胶质衍生的S1P激活EC S1P1受体，AKT和端粒酶，保护EC免受凋亡和诱导新生血管的影响。 AIM 1（体外）将确认并表征EC中S1P的端粒酶反应（激活和上调），并检验以下假设：神经元和神经胶质SPK2产生的S1P诱导端粒酶激活，从而介导EC保护和扩散。我们建议S1P1受体，AKT和热冲蛋白90（HSP90）在这些效果中起关键作用。 AIM 2（体内）将表明S1P受体激动剂前药FTY720增加了脑EC中的端粒酶表达，并扩展了初步发现，表明该药物在MCAO之前或之后施用时会降低梗塞大小。 Using transgenic mice expressing dominant negative Akt under the control of an EC-specific promoter, or mice lacking either the catalytic subunit or the RNA template of telomerase, we will test the hypothesis that the protective effect of FTY720 is related to Akt and telomerase activation in EC, and that this effect does not depend on the catalytic activity of telomerase (FTY720 should protect in RNA template淘汰赛）。该项目将研究一个新型系统，该系统可以在中风后提供长期改善的EC功能，并作为中风治疗的新目标。