Exercise, neurotrophins and axon regeneration in the PNS

运动、神经营养因子和三七总皂甙中的轴突再生

• 批准号: 7175528
• 负责人: Arthur W. English
• 金额: $ 30.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-19 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175528
• 关键词: Address; Afferent Neurons; Allografting; Animal Model; Attention; Axon; Biological Models; Brain; Brain-Derived Neurotrophic Factor; Chromosome Pairing; Clinical; Confocal Microscopy; Dependence; Development; Effectiveness; Electric Stimulation; Exercise; Goals; Growth; Health; Hour; Injury; Intervention; Knockout Mice; Label; Lesion; Mediating; Methods; Modality; Motor; Motor Endplate; Motor Neurons; Mus; Muscle; Natural regeneration; Nerve; Nervous System Trauma; Neuraxis; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Operative Surgical Procedures; Outcome; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Production; Proteins; Recovery of Function; Research Personnel; Sensory; Signal Transduction; Skeletal Muscle; Specificity; Speed; Spinal; Spinal Cord; Synapses; Therapeutic; Time; Time Study; Training; Transgenic Mice; Transgenic Organisms; Treatment Protocols; Walking; Week; axon growth; axon regeneration; base; cost; day; design; disability; functional outcomes; improved; injured; neural circuit; neurotrophic factor; novel; programs; receptor; reinnervation; repaired; research study; sedentary; synaptogenesis

DESCRIPTION (provided by applicant): The two reasons most often given for the generally poor functional outcomes observed after peripheral nervous system (PNS) injury are that regenerating axons in peripheral nerves grow slowly and that muscles are often reinnervated by functionally inappropriate motoneurons. Electrical stimulation (ES) of the cut nerve at the time of its surgical repair promotes a significant enhancement of the growth of regenerating axons that is mediated by neuronal neurotrophins. However, there are many circumstances in which ES could be used and ES also results in an increase in muscle reinnervation by functionally inappropriate motoneurons. Exercise promotes BDNF expression in the brain and spinal cord and this could result in a stimulation of the growth of regenerating axons. The goal of this project is to compare the effects of one form of exercise, treadmill training, to those of ES on axon regeneration in peripheral nerves. A combination of transgenic and knockout mice will be used as a novel model system to investigate whether an exercise- induced enhancement of the growth of regenerating axons is mediated by neuronal neurotrophins. By comparing the effects of treadmill training on axon regeneration directly to those produced by ES, we will evaluate whether the enhancement of axon regeneration produced is similar. Synapse re-formation is a critical part of functional recovery after injury to the PNS, and without intervention, it takes longer than it takes regenerating axons to grow sufficiently to reach the muscles. We will compare the effect of ES and treadmill training on the time course of neuromuscular synapse re-formation in transgenic mice. Because it activates motoneurons naturally via their intrinsic neural circuits, exercise could be a way of enhancing regeneration with less functionally inappropriate reinnervation of muscles than noted with ES. The specificity of reinnervation of four different muscle targets will be compared, using retrograde fluorescent labeling methods, in untreated, electrically stimulated, and treadmill trained mice. Exercise has the potential to ameliorate both of the major issues contributing to poor functional recovery from lesions to the PNS. Its potential for clinical use with low cost and very high benefit is great. This project provides a unique opportunity to provide answers important to questions that will strengthen the basis for such clinical use.

描述（由申请人提供）：周围神经系统（PNS）损伤后观察到的功能结果普遍较差的两个最常见原因是周围神经中的再生轴突生长缓慢以及肌肉经常由功能不适当的运动神经元重新支配。在手术修复时对切断的神经进行电刺激（ES）可显着增强由神经元神经营养素介导的再生轴突的生长。然而，在许多情况下可以使用 ES，并且 ES 还会导致功能不适当的运动神经元引起的肌肉再神经支配增加。运动促进大脑和脊髓中 BDNF 的表达，这可能会刺激再生轴突的生长。该项目的目标是比较一种运动形式（跑步机训练）与 ES 对周围神经轴突再生的影响。转基因和基因敲除小鼠的组合将被用作新的模型系统，以研究运动诱导的再生轴突生长的增强是否是由神经元神经营养蛋白介导的。通过直接比较跑步机训练对轴突再生的影响与 ES 产生的影响，我们将评估所产生的轴突再生的增强是否相似。突触重建是三七总皂甙损伤后功能恢复的关键部分，如果不进行干预，它需要比再生轴突充分生长以到达肌肉所需的时间更长的时间。我们将比较 ES 和跑步机训练对转基因小鼠神经肌肉突触重建时间过程的影响。因为它通过运动神经元的内在神经回路自然地激活运动神经元，所以运动可能是一种增强再生的方法，与 ES 相比，肌肉功能性不适当的神经支配更少。将使用逆行荧光标记方法，在未经治疗、电刺激和跑步机训练的小鼠中比较四种不同肌肉目标的神经支配的特异性。运动有可能改善导致 PNS 损伤功能恢复不良的两个主要问题。其成本低、效益高的临床应用潜力巨大。该项目提供了一个独特的机会来提供重要问题的答案，从而加强此类临床应用的基础。