The Effects of GDNF on Peripheral Nerve Regeneration

GDNF对周围神经再生的影响

• 批准号: 7755025
• 负责人: SUSAN E MACKINNON
• 金额: $ 36.52万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755025
• 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; Proteins; Recovery; Regulation; Relative (related person); Research Personnel; Role; Route; Schwann Cells; Sensory; Side; Signal Pathway; Skeletal Muscle; Source; Specificity; Surgeon; Surgical Management; Testing; Time; Transcription Factor AP-1; Transcriptional Regulation; Transgenic Mice; Transgenic Model; Transgenic Organisms; Wild Type Mouse; axon regeneration; base; clinical application; clinically relevant; glial cell-line derived neurotrophic factor; improved; in vivo; injured; injury and repair; nerve injury; neurotrophic factor; overexpression; programs; promoter; reconstruction; regenerative; 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、细致的手术重建，近端外伤周围神经仍能恢复 伤势往往很差。失去神经支配一年以上的肌肉的特点是纤维化和丧失 即使再生轴突到达电机端板，也无法有效地重新受神经支配 目标。能够增加轴突再生速率并适当引导的药剂 损伤后沿着运动路径再生运动轴突和沿着感觉路径再生感觉轴突 寻求优化周围神经损伤的恢复。外源性给予神经营养剂 因子和神经亲免素配体已证明具有不同的神经再生功效。胶质源性 神经营养因子（GDNF）是一种特别有效的运动神经元存活因子，已显示出一些益处 周围神经损伤后的恢复。然而，GDNF 对速率和特异性（运动 与感觉）轴突再生的重要性，其给药途径的重要性及其机制 其作用尚未在临床相关的周围神经损伤范例中经过严格的测试。致地址 针对这些问题，我们开发了两种不同的转基因小鼠品系，它们具有明确的特征模式 GDNF 在中枢神经系统或周围肌肉中过度表达。此外，这些小鼠表达 大多数运动和感觉轴突中的黄色荧光蛋白或绿色荧光增强 仅在少数外周运动神经中添加蛋白质，以实现神经再生的连续跟踪。在我们具体的 我们的目的是使用这些小鼠模型来研究中枢或外周 GDNF 的神经增强作用 神经损伤后过度表达。在目标 1a 和 1b 中，中枢或神经元的神经再生效应 比较近端和远端外周神经挤压和外周 GDNF 过度表达 从形态和功能上修复横断损伤。我们还将研究GDNF介导的 下游信号通路和 GDNF 介导的神经转录调控 再生。在目标 2a 中，中枢和外周 GDNF 过度表达的神经增强作用 在用神经移植或延迟方式修复的横断损伤中评估来源 向侧面修复。在目标 2b 中，我们研究了 GDNF 和 FK506 对神经再生的叠加效应 坐骨神经横断损伤端到端修复后的组织学和机制。此外 建立 GDNF 递送途径，外周或中枢，这将最有效地刺激 周围神经损伤后的再生，在目标 3 中，我们利用我们的转基因模型来研究优先运动 神经再支配——一个与周围神经外科医生具有极大临床相关性的概念。我们将确定 哪种营养支持来源（目标来源或途径来源）对指导再生影响最大 轴突到适当的目标。