MECHANISMS OF PREFERENTIAL MOTOR REINNERVATION

描述（由申请人提供）：外周神经是感觉信息从外周传递到中枢神经系统（CNS）的通路，运动指令从CNS传递到肌肉。周围神经损伤导致感觉和运动的丧失。随着外周轴突再生，它们经常进入不适当的通路，导致皮肤轴突到肌肉和运动轴突到皮肤。由于这一点和其他限制因素，只有10%的成年人将经历周围神经修复后恢复接近正常的功能。该建议的目的是改善周围神经损伤的结果。优先运动神经再支配（PMR），即运动轴突在混合神经中再生返回肌肉的趋势，是我们特定目标的起点。目的I探讨PMR的机制。虽然修剪运动轴突侧支从不正确的途径导致早期PMR，运动轴突再生较慢，似乎直接识别运动通路。了解这种情况发生的机制可以帮助我们设计策略来改善特异性，从而改善结果。这个目标还使用了在神经元中表达荧光蛋白的小鼠，以评估运动轴突在探索远端残端时的行为。它们对不同环境的反应应该提供途径识别和/或修剪行为的形态学证据。目的II着重于电刺激的效果，它可以增强感觉和运动再生。这一目标将定义DRG中受刺激影响的神经元类型，并确定这些神经元重新神经支配肌肉与皮肤的特异性。该目标还将探索有关刺激的时机，持续时间和功能后果的临床重要问题，并使用荧光小鼠来定义受刺激轴突的形态。目的III探讨退变的感觉神经和运动神经优先支持感觉轴突和运动轴突再生的可能性。运动轴突在以前的实验中对皮肤和肌肉通路的反应不同，最近的PCR研究提供了营养因子在退化的背根和腹根中差异上调的证据。新鲜和预变性的前根将被评估为感觉和运动轴突的移植物，并将进一步阐述背根和前根中营养因子的差异表达。

DESCRIPTION (provided by applicant): Peripheral nerve is the pathway through which sensory information is conveyed from the periphery to the central nervous system (CNS), and commands for movement are conveyed from the CNS to muscle. Peripheral nerve injury results in the loss of both feeling and movement. As peripheral axons regenerate they often enter inappropriate pathways, leading cutaneous axons to muscle and motor axons to skin. As a result of this and other limiting factors, only 10% of adults will experience restoration of near-normal function after peripheral nerve repair. The goal of this proposal is to improve the outcome of peripheral nerve injury. Preferential Motor Reinnervation (PMR), the tendency for motor axons regenerating in mixed nerve to return to muscle, is the starting point for our specific aims. Aim I explores the mechanism underlying PMR. Although pruning of motor axon collaterals from incorrect pathways leads to early PMR, motor axons that regenerate more slowly appear to recognize motor pathways directly. Understanding the mechanism by which this occurs could help us design strategies to improve specificity and therefore outcome. This aim also uses mice engineered to express fluorescent protein in their neurons to evaluate the behavior of motor axons as they explore the distal stump. Their response to different environments should provide morphologic evidence of pathway recognition and/or pruning behavior. Aim II focuses on the effects of electrical stimulation, which enhances both sensory and motor regeneration. This aim will define the types of neuron in the DRG that are affected by stimulation, and determine the specificity with which these neurons reinnervate muscle vs. skin. The aim will also explore clinically important questions regarding the timing, duration, and functional consequences of stimulation, and use the fluorescent mice to define the morphology of stimulated axons. Aim III Investigates the possibility that degenerating sensory and motor nerve may preferentially support the regeneration of sensory or motor axons respectively. Motor axons have responded differently to cutaneous and muscle pathways in previous experiments, and recent PCR studies have provided evidence of differential upregulation of trophic factors in degenerating dorsal and ventral root. Fresh and predegenerated ventral root will be evaluated as graft for sensory and motor axons, and differential expression of trophic factors in dorsal and ventral roots will be further elaborated.