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.

尽管及时和细致的手术重建，恢复近端创伤周围神经， 受伤的人往往很穷。失神经支配超过一年的肌肉的特征是纤维化和丧失神经纤维。 即使再生轴突到达它们的运动神经， 目标的能够增加轴突再生速率并适当引导轴突再生的试剂， 损伤后沿运动路径再生运动轴突和沿感觉路径再生感觉轴突， 试图优化周围神经损伤的恢复。外源性给予神经营养素 因子和神经亲免疫素配体已经证明了可变的神经再生功效。胶质衍生 神经营养因子（GDNF）是一种特别有效的运动神经元存活因子，已显示出一定的益处 周围神经损伤后的恢复。然而，GDNF对运动神经元的速率和特异性（运动神经元）的影响， vs.轴突再生的感觉），其给药途径的重要性，及其机制， 作用尚未在临床相关的外周神经损伤范例中进行严格测试。解决 这些问题，我们已经开发了两种不同的转基因小鼠，具有良好的特征模式， GDNF在中枢神经系统或外周肌肉中过度表达。此外，这些小鼠表达 增强的黄色荧光蛋白在他们的大部分运动和感觉轴突或绿色荧光 蛋白质仅在少数外周运动神经中，以实现神经再生的连续跟踪。对我国所在 目的利用这些小鼠模型研究中枢或外周GDNF的神经增强作用 神经损伤后的过度表达。在目标1a和1b中，研究了中枢或中枢神经系统的神经再生作用。 在近端和远端周围神经挤压之间比较外周GDNF过表达， 在形态和功能上修复横断损伤。我们还将研究GDNF介导的 神经元下游信号通路和GDNF介导的转录调控 再生在aim 2a中，GDNF过表达的中枢和外周神经元的神经增强作用被观察到。 在用神经移植物或神经移植物以急性或延迟方式修复的横断损伤中评价神经源， 侧修复。在目的2b中，我们研究了GDNF和FK 506对神经再生的相加作用， 坐骨神经横断损伤端对端修复后组织学和机械学变化。除了 建立GDNF递送途径，外周或中枢，这将最有效地刺激 目的3：利用我们的转基因模型研究周围神经损伤后的优先运动， 神经再支配-一个与周围神经外科医生具有极端临床相关性的概念。我们将决定 营养支持的来源，目标或途径来源在指导再生中影响最大 轴突到合适的目标。