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.

项目摘要/摘要 在过去的二十年 导致在不同脱脂的缺血性中风的患者数量大幅增加 不幸的是，尽管这个问题的幅度是 缺血性损伤后神经卫星的过程被理解为有效的治疗方法 促进缺血性中风幸存者中神经恢复的策略。 对突触结构和功能的影响，随着神经病学缺陷的发展的发展。 缺血性中风后的神经恢复重新造成新的突触和/或 维修那些因缺血性损伤而损坏的人。 轴突胸部和突触后的粘合剂接触的恢复和/或从头形成 末端，并由膜结合的粘附蛋白之间的相互作用介导 （N-钙粘蛋白或NCAD）是一种基于突触中的粘附蛋白，它形成粘合剂接触 突触前末端和尿蛋白酶型纤溶酶原激活剂（UPA）之间 结合TOTS受体（UPAR）催化纤溶酶原Intmin的转化并激活细胞 信号通路，促进细胞存活，增殖和运动。 应用我们发现，UPA是从皮质神经元的突触前末端释放的， 缺血性中风的恢复阶段，该UTS受体（UPAR）的结合促进了修复 在这种续签中受到缺血性损伤的轴突和树突。 内源性或重组UPAR的结合通过诱导您促进突触修复 NCAD介导的粘合剂接触的形成，突触前末端和已介导的粘合剂接触 受到缺血性损害的损害。 调节NCAD在突触中的表达和功能，并测试UPA促进的假设 通过诱导NCAD介导的重建/或格式接触来诱导突触恢复 轴突胸子和遭受缺血性损伤的神经元的突触后末端之间。 将研究UPA对规范Wnt-β-catenin途径的影响。 脑缺血的脑缺血，以研究UPA诱导的NCAD介导的Wnt-β-catenin途径的激活 缺血性损伤后促进突触修复和神经恢复。