Axonal growth and guidance for nervous system repair

描述（由申请人提供）：每年因损伤进行的周围神经修复手术超过50,000例（国家卫生统计中心，1995年）。这些数据不包括肿瘤切除或前列腺切除术引起的神经损伤。即使周围神经再生良好，只有10 - 20%的患者接受手术修复外伤性神经损伤显示良好到非常好的功能恢复。恢复失败的高发生率是由于再生轴突到其目标的错误路由。该建议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。这些研究将探讨战略性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向适当的神经分支或脊髓生长方面的作用。本课题的所有实验都将采用生物可吸收性植入物诱导神经修复和定向表达引导因子的基因。这些实验的第一个目的是探索使用神经营养因子GDNF、BDNF和NT-3诱导感觉轴突亚群跨越6毫米背根损伤间隙并进入脊髓的再生。行为分析将检查机械感受和本体感受反应的恢复。实验的第二到第四个目标将使用股神经模型来检查周围神经大面积切除病变后的靶向性。股神经包含感觉轴突和运动轴突，通常分为感觉分支（隐神经）和运动分支（股四头肌）。在割伤后，再生大多是随机的，其中每个分支将包含皮肤感觉轴突和运动轴突的混合物。第二个目标是引导感觉轴突进入隐神经分支，而不是运动神经分支。在本研究中，对感觉轴突具有生长吸引力的选择性神经营养因子将在隐神经中表达，而对感觉轴突具有特异性抑制作用的排斥因子将在运动分支中表达。第三个目的是研究神经营养因子和排斥因子对再生运动和本体感觉轴突进入运动分支而不是隐神经的选择性引导。第四个目标旨在结合目标2和目标3的因素，以优化目标定向再生到更正常的模式。这一目标也将开发和测试临床相关的生物可吸收神经袖带，以缓慢释放引导因子。这项拨款提案旨在更好地定义影响成人PNS内轴突再生和引导的分子机制，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.