Axonal growth and guidance for nervous system repair

描述（由申请人提供）：由于损伤，每年进行超过50，000次外周神经修复手术（国家卫生统计中心，1995年）。这些数据不包括由于肿瘤切除或神经切除术造成的神经损伤。尽管周围神经再生良好，但只有10%至20%的接受手术修复创伤性神经损伤的患者表现出极好至非常好的功能恢复。失败恢复的高发生率是由于再生轴突向其目标的错误路由。该提案旨在更好地了解指导这种生长以增加成人功能恢复的潜在机制。这些研究将检查战略表达的神经营养因子和化学排斥因子在指导感觉和运动轴突生长到适当的神经分支或脊髓中的作用。本方案中的所有实验将使用生物可吸收植入物诱导神经修复和导向因子的靶向基因表达。这些实验的第一个目的将探索使用神经营养因子GDNF、BDNF和NT-3来诱导感觉轴突亚群的再生穿过6 mm背根损伤间隙并进入脊髓。行为分析将检查机械感受和本体感受反应的恢复。实验的第二至第四个目的将使用股神经模型来检查对该神经的大切除损伤后的外周神经靶向。股神经包含感觉和运动轴突，其通常分离成感觉分支（隐神经）和运动分支（股四头肌）。切割损伤后，再生大多是随机的，其中每个分支将包含皮肤感觉和运动轴突的混合物。第二个目标是引导感觉轴突进入隐分支而不是运动分支。在这项研究中，选择性的神经营养因子，是生长的感觉轴突的吸引力将在隐神经和排斥因子，是特异性抑制感觉轴突的运动分支中表达。第三个目标将检查神经营养因子和排斥因子，用于选择性引导再生的运动和本体感受轴突进入运动分支而不是隐神经。第四个目标被设计为结合来自目标2和3的因素，以将目标定向再生优化为更正常的类似模式。这一目标还将开发和测试临床相关的生物可吸收神经袖带，用于缓慢释放引导因子。这项拨款提案旨在更好地定义影响成年PNS内轴突再生和指导的分子机制，最终目标是指导和组织再生到更合适的目标，同时阻止异常连接。

DESCRIPTION (provided by applicant): Over 50,000 peripheral nerve repair procedures are performed a year due to injury (National Center for Health Statistics, 1995). These data do not include nerve injury due to tumor resection or prostatectomies. Even though the peripheral nerves regenerate well, only 10 to 20% of patients that undergo surgery to repair traumatic nerve injuries show excellent to very good recovery of function. The high incidence of failed recovery is due to the misrouting of regenerating axons to their targets. This proposal is designed to better understand the potential mechanisms that direct this growth to increase functional recovery in adults. The studies will examine the role strategically expressed neurotrophins and chemorepulsive factors will have on directing the growth of sensory and motor axons into appropriate nerve branches or the spinal cord. All the experiments in this proposal will use bioreabsorbable implants to induce nerve repair and targeted gene expression of guidance factors. The first aim of these experiments will explore the use of the neurotrophins GDNF, BDNF, and NT-3 to induce the regeneration of sensory axon subsets across a 6mm dorsal root lesion gap and into the spinal cord. Behavioral analysis will examine recovery of mechanoreceptive and proprioceptive responses. The second to forth aim of experiments will use the femoral nerve model to examine peripheral nerve targeting after large excision lesions to that nerve. The femoral nerve contains both sensory and motor axons that normally segregate into a sensory branch (saphenous) and a motor branch (quadriceps femoris). After cut injury, regeneration is mostly random, in which each branch will contain a mixture of both cutanteous sensory and motor axons. The second aim will be to guide sensory axons into the saphenous branch and not the motor branch. In this study, selective neurotrophins that are growth attractive for sensory axons will be expressed in the saphenous nerve and repulsive factors that are specifically inhibitory to sensory axons expressed in the motor branch. The third aim will examine neurotrophins and repulsive factors for the selective guidance of regenerating motor and proprioceptive axons into the motor branch and not the saphenous nerve. The forth aim is designed to incorporate the factors from aim 2 and 3 to optimize target directed regeneration to more normal like patterns. This aim will also develop and test clinically relevant bioreabsorbable nerve cuffs for slow release of guidance factors. This grant proposal is designed to better define the molecular mechanisms that influence axonal regeneration and guidance within the adult PNS, with the ultimate goal of directing and organizing regeneration to more appropriate targets, while discouraging aberrant connections.