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: 10310509
• 负责人: Manuel Salvador Yepes
• 金额: $ 44.63万
• 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 2023-01-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310509
• 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.

项目概要/摘要 在过去的二十年里，急性缺血性中风死亡率显着下降，这反过来又降低了死亡率。 导致不同程度的缺血性中风患者存活率大幅增加 不幸的是，尽管这个问题很严重，但迄今为止，其背后的机制尚不清楚。 人们对缺血性损伤后的神经修复过程知之甚少，并且没有有效的治疗方法 促进缺血性中风幸存者神经功能恢复的策略具有有害性。 对与神经缺陷发展相关的突触结构和功能的影响。 缺血性中风后的神经恢复需要形成新的突触接触和/或 修复因缺血性损伤而受损的组织，这是一个高度动态的过程，始于缺血性损伤。 重建和/或从头形成轴突纽扣和突触后之间的粘附接触 末端，并由膜结合粘附蛋白之间的相互作用介导。 （N-钙粘蛋白或 NCAD）是一种在突触中大量存在的粘附蛋白，在突触中形成粘附接触 突触前和突触后末端之间的尿激酶型纤溶酶原激活剂 (uPA) 是一种丝氨酸蛋白酶。 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。 应用我们发现uPA是在大脑皮层神经元突触前末梢释放的 缺血性中风的恢复阶段，uPA 与其受体 (uPAR) 的结合可促进修复 因缺血性损伤而受损的轴突和树突的数量在此更新应用中，我们将检验该假设。 内源性或重组uPA与uPAR的结合通过诱导突触修复来促进突触修复 在突触前和突触后末端之间形成 NCAD 介导的粘附接触 为了实现这一目标，首先我们将研究 uPA 的机制。 调节突触中 NCAD 的表达和功能，并检验 uPA 促进的假设 通过诱导 NCAD 介导的重建和/或新粘附接触的形成来恢复突触 在遭受缺血性损伤的神经元的轴突束和突触后末端之间 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。 脑缺血的研究，以研究 uPA 是否诱导 NCAD 介导的 Wnt-β-Catenin 通路激活 促进缺血性损伤后的突触修复和神经恢复。