The Effects of GDNF on Peripheral Nerve Regeneration

尽管及时细致地进行了手术重建，但近端损伤周围神经的恢复 受伤的情况往往很糟糕。肌肉失神经一年以上的特点是纤维化和丧失 马达终板，即使再生轴突到达其马达也不能有效地重新支配 目标。能够提高轴突再生率并适当引导的药物 损伤后沿着运动路径再生的运动轴和沿着感觉路径再生的感觉轴突 寻求从周围神经损伤中最佳恢复。神经营养的外源性给药 因子和神经免疫亲和素配体已显示出不同的神经再生效果。神经胶质来源 神经营养因子(GDNF)是一种特别有效的运动神经元生存因子，已显示出一些好处 在周围神经损伤后的康复中。然而，GDNF对发生率和特异性(运动)的影响 VS感觉)轴突再生的重要性，其给药途径的重要性，以及它的机制 作用还没有在临床相关的周围神经损伤范例中得到严格的测试。致信地址 在这些问题上，我们已经开发出两个不同的转基因小鼠系，它们具有良好的特征模式 GDNF在中枢神经系统或外周肌肉中过表达。此外，这些小鼠还表达了 在他们的大多数运动和感觉神经轴突中增强的黄色荧光蛋白或绿色荧光 仅在少数外周运动神经中存在蛋白质，以实现对神经再生的连续跟踪。在我们的特定情况下 目的我们利用这些小鼠模型来研究中枢或外周GDNF的神经增强作用 神经损伤后的过度表达。在AIMS 1a和1b中，中枢或 比较周围神经近端和远端神经卡压后GDNF的过度表达 修复了横断性损伤的形态和功能。我们还将研究GDNF介导的 神经参与的下游信号通路和GDNF介导的转录调控 再生。在AIM 2a中，中枢和外周GDNF的过度表达对神经功能的增强作用 对急性或延迟神经移植修复的横断性损伤的来源进行评估。 边修边修。在目标2b中，我们研究了GDNF和FK506对神经再生的相加作用 坐骨神经横断性损伤端到端修复后的组织学和力学研究。除了……之外 建立GDNF外周或中枢传递途径，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。 神经再生--这是一个对周围神经外科医生具有极端临床意义的概念。我们将决定 靶向或途径来源的营养支持对引导再生的影响最大 轴突到达它们合适的目标。

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.