MECHANISMS OF PREFERENTIAL MOTOR REINNERVATION

描述（由申请人提供）：外周神经是将感觉信息从外周传递到中枢神经系统（CNS），并将运动命令从中枢神经系统传递到肌肉的途径。周围神经损伤导致感觉和运动的丧失。当外周轴突再生时，它们经常进入不适当的通路，导致皮肤轴突到肌肉，运动轴突到皮肤。由于这个和其他限制因素，只有10%的成年人在周围神经修复后能恢复到接近正常的功能。本研究的目的是改善周围神经损伤的预后。优先运动神经再生（PMR）是混合神经中运动轴突向肌肉再生的趋势，是我们具体目标的起点。目的1探讨PMR的机制。虽然从不正确的通路上修剪运动轴突侧枝会导致早期PMR，但再生较慢的运动轴突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提高特异性，从而提高结果。该目的还利用在小鼠神经元中表达荧光蛋白的基因工程来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通路识别和/或修剪行为的形态学证据。目的II侧重于电刺激的效果，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，并确定这些神经元对肌肉和皮肤的再神经支配的特异性。目的还将探讨有关刺激的时间，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。目的三：探讨退行性感觉神经和运动神经分别优先支持感觉轴突和运动轴突再生的可能性。在以前的实验中，运动轴突对皮肤和肌肉通路的反应不同，最近的PCR研究提供了退化的背根和腹根中营养因子差异上调的证据。将评价新鲜和预退化的腹根作为感觉轴突和运动轴突的移植物，并进一步阐述背根和腹根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.