The Effects of GDNF on Peripheral Nerve Regeneration

GDNF对周围神经再生的影响

• 批准号: 7276562
• 负责人: SUSAN E MACKINNON
• 金额: $ 37.25万
• 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/7276562
• 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

DESCRIPTION (provided by applicant): 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 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 or end- 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. We will determine which source of trophic support, target- or pathway-derived has the most influence in directing regenerating axons to their appropriate targets.

描述（由申请人提供）：尽管及时且细致的手术重建，但近端创伤性周围神经损伤后的恢复通常很差。被剥离一年多的肌肉的特征是纤维化和运动端板的损失，即使再生轴突达到其运动靶标，也无法有效地加剧。能够提高轴突再生速率并适当地指导电动机轴突沿电动路径和感觉轴突降低损伤后的感觉路径的速度，以优化从周围神经损伤中恢复的恢复。神经营养因子和神经免疫蛋白配体的外源给药表现出可变的神经加快疗效。神经胶质神经营养因子（GDNF）是一种特别有效的运动神经元存活因子，在周围神经损伤后显示出一些益处。但是，GDNF对轴突再生的速率和特异性（运动与感觉）的影响，其给药途径的重要性以及其作用机理的影响尚未在临床上相关的外周神经损伤范式中进行严格测试。为了解决这些问题，我们已经开发了两种不同的转基因小鼠行，在中枢神经系统或周围肌肉中具有良好的GDNF过表达模式。此外，这些小鼠在其大多数运动轴突和感觉轴突或绿色荧光蛋白中仅表达增强的黄色荧光蛋白，或者仅在几个外围运动神经中表达了绿色荧光蛋白，以实现神经再生的串行跟踪。在我们的具体目的中，我们使用这些鼠模型来研究神经损伤后中央或周围GDNF过表达的神经性效应。在AIMS 1a和1b中，比较了中央或周围GDNF过表达的神经加快作用在近端和远端周围神经压伤和远端外周神经挤压和修复的横切损伤之间。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，从中央和周围来源的GDNF过表达的神经性效应以急性或延迟的方式用神经移植或末端修复来评估。在AIM 2B中，我们研究了GDNF和FK506对坐骨神经横向损伤端到端修复后的组织学和机械再生神经再生的添加作用。除了建立GDNF递送途径外，外周或中央 - 这将最有效地刺激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的运动性运动 - 这是一种具有极端临床相关性的概念，具有极端的临床相关性。我们将确定哪种营养支持来源，目标或途径衍生的源自将再生轴突指向其适当的靶标具有最大的影响。