Urokinase-type Plasminogen Activator in the Ischemic Brain

缺血脑中的尿激酶型纤溶酶原激活剂

• 批准号: 10116720
• 负责人: Manuel Salvador Yepes
• 金额: $ 43.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10116720
• 关键词: Actins; Acute; Adhesives; Animal Model; Area; Attenuated; Axon; Binding; Brain; Cadherins; Cell Survival; Cerebral Ischemia; Cerebrum; Cytoskeleton; Data; Dendrites; Dendritic Spines; Development; Event; Funding; Genes; Genetic Transcription; Goals; Intravenous; Ischemic Stroke; Lead; Link; Mediating; Membrane; N-Cadherin; Necrosis; Neurologic Deficit; Neurological outcome; Neuronal Injury; Neurons; Nuclear Translocation; Pathway interactions; Patients; Pharmacology; Phase; Plasmin; Plasminogen; Presynaptic Terminals; Process; Proteins; Publishing; Recombinants; Recovery; Serine Protease; Signal Pathway; Signal Transduction; Structure; Synapses; Testing; Tissues; Up-Regulation; Urokinase; armadillo proteins; base; beta catenin; brain repair; cell motility; dimer; disability; functional outcomes; hypoxic ischemic injury; improved; ischemic injury; member; monomer; mortality; neurological recovery; novel; postsynaptic; receptor; repaired; stroke survivor; synaptic function; synaptogenesis; therapeutically effective; tool

PROJECT SUMMARY/ABSTRACT The last two decades have witnessed a significant decrease in acute ischemic stroke mortality, that in turn has caused a substantial increase in the number of patients that survive an ischemic stroke with different degrees of disability. Unfortunately, despite the magnitude of this problem, to this date the mechanisms that underlie the process of neurorepair following an ischemic injury are poorly understood, and there is no effective therapeutic strategy to promote neurological recovery among ischemic stroke survivors. Cerebral ischemia has a harmful impact on synaptic structure and function associated with the development of neurological deficits. Hence, neurological recovery following an ischemic stroke requires the formation of new synaptic contacts and/or the repair of those damaged by the ischemic injury. This is a highly dynamic process that begins with the reestablishment and/or de novo formation of adhesive contacts between axonal boutons and postsynaptic terminals, and is mediated by the interaction between membrane-bound adherent proteins. Neuronal cadherin (N-Cadherin or NCAD) is an adherent protein abundantly found in the synapse, where it forms adhesive contacts between the pre- and postsynaptic terminals. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin and activates cell signaling pathways that promote cell survival, proliferation and motility. In the previous funding cycle of this application we found that uPA is released from the presynaptic terminal of cerebral cortical neurons during the recovery phase from an ischemic stroke, and that binding of this uPA to its receptor (uPAR) promotes the repair of axons and dendrites damaged by the ischemic injury. In this renewal application we will test the hypothesis that binding of either endogenous or recombinant uPA to uPAR promotes synaptic repair by inducing the formation of NCAD-mediated adhesive contacts between the pre- and postsynaptic terminals that have been damaged by an ischemic injury. To accomplish this goal, first we will study the mechanism whereby uPA regulates the expression and function of NCAD in the synapse, and test the hypothesis that uPA promotes synaptic recovery by inducing NCAD-mediated reestablishment and/or formation of new adhesive contacts between axonal boutons and postsynaptic terminals of neurons that have suffered an ischemic injury. Then, we will investigate the effect of uPA on the canonical Wnt-β-Catenin pathway. Finally, we will use an animal model of cerebral ischemia to investigate if uPA-induced NCAD-mediated activation of the Wnt-β-Catenin pathway promotes synaptic repair and neurological recovery after an ischemic injury.

项目总结/摘要 在过去的二十年里，急性缺血性卒中死亡率显著下降，这反过来又使 导致了不同程度的缺血性中风患者存活率的大幅增加。 残疾。不幸的是，尽管这个问题很严重，但迄今为止， 缺血性损伤后的神经修复过程知之甚少， 促进缺血性卒中幸存者神经功能恢复策略。脑缺血有一个有害的 对突触结构和功能的影响与神经功能缺损的发展有关。因此，我们认为， 缺血性中风后的神经恢复需要新的突触接触的形成和/或 修复那些被缺血性损伤损伤的细胞。这是一个高度动态的过程， 轴突终扣和突触后神经元之间粘附接触的重新建立和/或从头形成。 末端，并通过膜结合的粘附蛋白之间的相互作用介导。神经元钙粘蛋白 N-钙粘蛋白（N-Cadherin或NCAD）是一种大量存在于突触中的粘附蛋白，在那里它形成粘附接触 在突触前和突触后末梢之间。尿激酶型纤溶酶原激活剂（uPA）是一种丝氨酸蛋白酶 在与其受体（uPAR）结合后，催化纤溶酶原转化为纤溶酶并激活细胞 促进细胞存活、增殖和运动的信号通路。在上一个融资周期中， 应用我们发现，uPA是释放从突触前末梢的大脑皮层神经元在 从缺血性中风恢复阶段，这种uPA与其受体（uPAR）的结合促进了修复 轴突和树突被缺血性损伤所破坏。在这个更新应用程序中，我们将测试假设 内源性或重组uPA与uPAR的结合通过诱导 NCAD介导的突触前和突触后末梢之间的粘附接触的形成， 因缺血性损伤而受损为了实现这一目标，首先我们将研究uPA 调节NCAD在突触中的表达和功能，并测试uPA促进突触形成的假设。 通过诱导NCAD介导的重新建立和/或形成新的粘附接触来恢复突触 在遭受缺血性损伤的神经元的轴突终末和突触后末端之间。然后我们 将研究uPA对经典Wnt-β-Catenin通路的影响。最后，我们将使用动物模型 研究uPA诱导的NCAD介导的Wnt-β-Catenin通路的激活 促进缺血性损伤后的突触修复和神经恢复。