Axonal growth and guidance for nervous system repair

描述(申请人提供)：每年因损伤而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)。这些数据不包括肿瘤切除或前列腺切除术造成的神经损伤。尽管周围神经再生良好，但在接受手术修复创伤性神经损伤的患者中，只有10%到20%的人表现出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错误地路由到它们的靶点。这项建议旨在更好地了解引导这种生长以促进成人功能恢复的潜在机制。这些研究将检验策略性表达的神经营养因子和化学排斥因子在引导感觉和运动轴突生长到适当的神经分支或脊髓上所起的作用。该方案中的所有实验都将使用可生物吸收的植入物来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来诱导感觉神经轴突亚群穿过6 mm的背根病变间隙并进入脊髓。行为分析将检查机械感受性和本体感觉反应的恢复。实验的第二个到第四个目标将使用股神经模型来检查周围神经在大范围切除损伤后的靶向。股神经包含感觉轴突和运动轴突，它们通常分为感觉支(隐神经)和运动支(股四头肌)。在切割伤后，再生大多是随机的，其中每个分支都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，而排斥因子则对运动分支中表达的感觉轴突具有特异性抑制作用。第三个目标将检查神经营养因子和排斥因子，以选择性地引导再生运动和本体感觉轴突进入运动分支，而不是隐神经。第四个目标旨在结合目标2和目标3中的因素，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上相关的生物可吸收神经袖带，用于指导因子的缓慢释放。这项拨款提案旨在更好地定义影响成年三叉神经节内轴突再生和指导的分子机制，最终目标是引导和组织再生到更合适的靶点，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.