The Effects of GDNF on Peripheral Nerve Regeneration

GDNF对周围神经再生的影响

• 批准号: 7386678
• 负责人: SUSAN E MACKINNON
• 金额: $ 36.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386678
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Address; Axon; Chronic; Data; Distal; FK506; Fibrosis; GDNF gene; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Histologic; Injury; Ligands; Mediating; Modeling; Motor; Motor Endplate; Motor Neurons; Motor Pathways; Mus; Muscle; Myogenin; Natural regeneration; Nature; Nerve; Nerve Crush; Nerve Regeneration; Neuraxis; Operative Surgical Procedures; Pathway interactions; Pattern; Peripheral; Peripheral Nerves; Peripheral nerve injury; Process; Protein Overexpression; Proteins; Rate; Recovery; Regulation; Relative (related person); Research Personnel; Role; Route; Schwann Cells; Sensory; Side; Signal Pathway; Skeletal Muscle; Source; Specificity; Surgeon; Surgical Management; Testing; Thinking; Time; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Mice; Transgenic Model; Transgenic Organisms; Wild Type Mouse; axon regeneration; base; clinical application; clinically relevant; concept; glial cell-line derived neurotrophic factor; improved; in vivo; injured; injury and repair; nerve injury; neurotrophic factor; programs; promoter; reconstruction; reinnervation; repaired; research study; sciatic nerve; transcription factor

Despite timely and meticulous surgical reconstruction, recovery following proximal traumatic peripheral nerve injuries is often poor. Muscles that are denervated for over a year are characterized by fibrosis and loss of motor end plates and cannot be effectively reinnervated even when regenerating axons reach their motor targets. Agents capable of increasing the rate of axonal regeneration and appropriately directing regenerating motor axons down motor paths and sensory axons down sensory paths after injury have been sought to optimize recovery from peripheral nerve injuries. The exogenous administration of neurotrophic factors and neuroimmunophilin ligands have demonstrated variable neuroregenerative efficacy. Glial-derived neurotrophic factor (GDNF) is an especially potent motor neuron survival factor that has shown some benefit in recovery following peripheral nerve injury. However, the effects of GDNF on the rate and specificity (motor vs. sensory) of axonal regeneration, the importance of its route of administration, and its mechanism of action have not been rigorously tested in clinically relevant peripheral nerve injury paradigms. To address these issues, we have developed two distinct lines of transgenic mice with well-characterized patterns of GDNF overexpression in the central nervous system or peripheral muscle. In addition, these mice express enhanced yellow fluorescent protein in most of their their motor and sensory axons or green fluorescent protein in only a few peripheral motor nerves to enable serial tracking of nerve regeneration. In our specific aims we use these murine models to study the neuroenhancing effects of central or peripheral GDNF overexpression following nerve injury. In aims 1a and 1b, the neuroregenerative effects of central or peripheral GDNF overexpression are compared between proximal and distal peripheral nerve crush and repaired transection injuries both morphologically and functionally. We will also study GDNF-mediated downstream signaling pathways and GDNF-mediated transcriptional regulation involved in nerve regeneration. In aim 2a the neuroenhancing effects of GDNF overexpression from central and peripheral sources are evaluated in transection injuries repaired in an acute or delayed fashion with nerve grafts orend- to-side repair. In aim 2b we study the additive effects of GDNF and FK506 on nerve regeneration both histologically and mechanistically following end-to-end repair of sciatic nerve transection injury. In addition to establishing the route of GDNF delivery, peripheral- or central-, that will most effectively stimulate regeneration after peripheral nerve injury, in aim 3 we utilize our transgenic model to study preferential motor reinnervation - a concept with extreme clinical relevance to peripheral nerve surgeons. Wewill determine which source of trophic support, target- or pathway-derived has the most influence in directing regenerating axons to their appropriate targets.

尽管及时且细致的手术重建，但近端创伤性周围神经后的恢复 伤害通常很差。被剥离一年多的肌肉的特征是纤维化和丧失 电动机端板，即使再生轴突到达电动机，也无法有效地恢复原状 目标。能够提高轴突再生速率并适当指导的代理 在损伤后向下的电动路径和感觉轴突向下再生运动轴突一直是 试图优化从周围神经损伤中恢复。神经营养的外源给药 因子和神经免疫性蛋白配体已表现出可变的神经增生功效。神经胶质 神经营养因子（GDNF）是一种特别有效的运动神经元的生存因子，显示出一定的益处 外周神经损伤后的恢复。但是，GDNF对速率和特异性的影响（电动机 与轴突再生的感觉，其给药途径的重要性以及其机制 在临床上相关的周围神经损伤范式中，尚未对作用进行严格的测试。解决 这些问题，我们开发了两种不同的转基因小鼠行 中枢神经系统或周围肌肉中的GDNF过表达。另外，这些小鼠表达 在它们的大部分电机和感觉轴突或绿色荧光中，增强黄色荧光蛋白 蛋白质仅在几个外围运动神经中才能实现神经再生的串行跟踪。在我们的具体情况下 目的我们使用这些鼠模型来研究中央或外围GDNF的神经性效应 神经损伤后的过表达。在目标1a和1b中，中央或 比较周围GDNF过表达在近端和远端周围神经压伤和 在形态和功能上修复了横断损伤。我们还将研究GDNF介导的 下游信号通路和GDNF介导的转录调节涉及神经 再生。在AIM 2A中，中央和周围的GDNF过表达的神经性效应 用神经移植物以急性或延迟方式修复的横切伤害评估来源。 待办事项维修。在AIM 2B中，我们研究了GDNF和FK506对神经再生的添加作用 坐骨神经横向损伤的端到端修复后，组织学和机械学上。此外 建立最有效刺激的GDNF传递（外围或中央）的途径 周围神经损伤后的再生，在AIM 3中，我们利用转基因模型来研究优先运动 重新支配 - 与周围神经外科医生具有极端临床相关的概念。我们将确定 哪种营养支持来源，目标或途径衍生的源 轴突达到其适当的目标。