MECHANISMS OF PREFERENTIAL MOTOR REINNERVATION

优先运动神经再生机制

• 批准号: 6614753
• 负责人: THOMAS M BRUSHART
• 金额: $ 38.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6614753
• 关键词: axon; dorsal root; electrostimulus; enzyme linked immunosorbent assay; fluorescence microscopy; innervation; laboratory mouse; laboratory rat; motor neurons; nerve injury; nervous system regeneration; neuronal guidance; neurotrophic factors; peripheral nervous system; polymerase chain reaction; spinal ganglion; ventral roots

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.

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）以及运动命令从 CNS 传递到肌肉的通路。周围神经损伤会导致感觉和运动丧失。当外周轴突再生时，它们经常进入不适当的路径，导致皮肤轴突通向肌肉，运动轴突通向皮肤。由于这一因素和其他限制因素，只有 10% 的成年人在周围神经修复后会恢复接近正常的功能。该提案的目标是改善周围神经损伤的结果。优先运动神经支配（PMR），即混合神经中运动轴突再生以返回肌肉的趋势，是我们特定目标的起点。目标 I 探索 PMR 的潜在机制。尽管从不正确的通路中修剪运动轴突侧支会导致早期 PMR，但再生较慢的运动轴突似乎可以直接识别运动通路。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。该目标还使用经过改造的小鼠在其神经元中表达荧光蛋白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提供途径识别和/或修剪行为的形态学证据。 Aim II 重点关注电刺激的效果，从而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支配肌肉与皮肤的特异性。该目标还将探索有关刺激的时间、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。目标 III 研究退化的感觉和运动神经可能分别优先支持感觉或运动轴突再生的可能性。在之前的实验中，运动轴突对皮肤和肌肉通路的反应不同，最近的 PCR 研究提供了退化背根和腹根中营养因子差异上调的证据。将评估新鲜和预退化的腹根作为感觉和运动轴突的移植物，并将进一步阐述背根和腹根营养因子的差异表达。