Exercise, neurotrophins, and axon regeneration in the PNS

运动、神经营养因子和 PNS 中的轴突再生

• 批准号: 8371360
• 负责人: Arthur W. English
• 金额: $ 33.91万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371360
• 关键词: Address; Affect; Androgen Receptor; Androgens; Animals; Area; Aromatase; Axon; Biological Assay; Brain-Derived Neurotrophic Factor; Clinical; Dependence; Effectiveness; Estradiol; Exercise; Female; Foundations; Generations; Genetic; Goals; Growth; Growth Cones; H-Reflex; Hour; Individual; Injury; Knock-out; Knockout Mice; Knowledge; Learning; Length; Locomotion; Measures; Medical; Methods; Monitor; Motor Neurons; Mus; Muscle; Natural regeneration; Nerve; Neural Conduction; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Operative Surgical Procedures; Optics; Patients; Pattern; Peripheral Nerves; Peripheral nerve injury; Public Health; Receptor Signaling; Recovery; Recovery of Function; Research; Role; Sex Characteristics; Signal Transduction; Simulate; Spinal Ganglia; Supervision; Technology; Testing; Testosterone; Therapeutic Uses; Time; Time Study; Training; Transgenic Mice; Translating; Translations; Walking; Woman; autocrine; axon growth; axon regeneration; base; cell type; design; disability burden; improved; in vivo; injured; kinematics; limb movement; male; men; neurotrophic factor; optogenetics; reinnervation; repaired; research study; restoration; sciatic nerve; sex; treatment effect

DESCRIPTION (provided by applicant): Axon regeneration in peripheral nerves is enhanced by exercise in the form of modest daily treadmill training. This project will study three inter-related aspects of exercise as a potential therapy for treatment of peripheral nerve injuries to help move it closer to actual translation. Marked sex differences in the efficacy of different training paradigms to promote axon regeneration exist and androgens are implicated in both sexes. In Aim 1, the androgen dependence of the effect of exercise will be studied in conditional androgen receptor knockout mice. The effects of different exercise paradigms on the lengths of regenerating axons, the numbers of neurons whose axons regenerate successfully, and the expression of brain derived neurotrophic factor (BDNF) and its receptor, trkB, in motoneurons, dorsal root ganglion neurons, and growth cones of regenerating axons will be studied both in systemic and neuron-specific knockouts. As a therapy, different exercise paradigms will be needed for use when different nerves are injured. Establishing guiding principles for their design will be important. The most obvious of these principles may be that the activity of neurons whose axons are regenerating is both necessary and sufficient for the enhancement of regeneration produced by the exercise, but this has not been studied in vivo. In the experiments in Aim 2, axotomized neurons will be activated directly using optogenetic technologies, to simulate their activity during treadmill training in male and female mice, and the sufficiency of this activation will be assayed by measuring the growth of regenerating axons and the expression of BDNF and trkB in neurons and growth cones. Using similar technologies in different mice, neuronal activity will be blocked during exercise and the effects assayed similarly to determine the requirement for activity for the effects of exercise. Whether exercise or optical activation of neurons that results in enhanced axon regeneration also leads to improved functional recovery will be studied in Aim 3. Nerve conduction studies will be used to monitor the time course of muscle reinnervation and H reflex restoration in exercised mice and optically activated mice. Kinematic analyses of limb movements during walking on different slopes will be used to measure these effects on functional recovery behaviorally Effects of sex and training/activation paradigm will be studied separately. This potential therapeutic use of exercise addresses an important public health issue. It is low-tech and requires only modest supervision by skilled practitioners. Patients can assume a lot of the responsibility for their own functional recovery. At the end of this study we will have acquired evidence in support of three significant aspects of the efficacy of exercise that will add to its translational promise. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because there are more than 100,000 new traumatic peripheral nerve injuries in the US each year, only a very small percentage of affected individuals ever recover full function, and there is no medical (non surgical) treatment for them. The scientific discoveries expected from the experiments in this proposal will represent new knowledge that could be applied to reduce the burdens of disability for these victims.

描述（由申请人提供）：通过适度的日常跑步机训练形式的锻炼可以增强周围神经的轴突再生。该项目将研究运动的三个相互关联的方面，作为治疗周围神经损伤的潜在疗法，以帮助其更接近实际的转化。不同训练模式促进轴突再生的功效存在明显的性别差异，并且雄激素与两性有关。在目标 1 中，将在条件性雄激素受体基因敲除小鼠中研究运动效果的雄激素依赖性。将在系统和神经元特异性敲除中研究不同运动模式对再生轴突长度、轴突成功再生的神经元数量以及运动神经元、背根神经节神经元和再生轴突生长锥中脑源性神经营养因子（BDNF）及其受体trkB表达的影响。作为一种治疗方法，当不同的神经受伤时，需要使用不同的运动模式。为其设计建立指导原则非常重要。这些原理中最明显的可能是，轴突正在再生的神经元的活动对于增强运动产生的再生来说既是必要的也是充分的，但这尚未在体内进行研究。在目标2的实验中，将使用光遗传学技术直接激活轴突神经元，以模拟雄性和雌性小鼠在跑步机训练期间的活动，并通过测量再生轴突的生长以及神经元和生长锥中BDNF和trkB的表达来分析这种激活的充分性。在不同的小鼠中使用类似的技术，神经元活动将在运动过程中被阻断，并且对效果进行类似的分析 确定运动效果所需的活动量。目标 3 将研究神经元的运动或光学激活是否会导致轴突再生增强，从而改善功能恢复。神经传导研究将用于监测运动小鼠和光学激活小鼠的肌肉神经支配和 H 反射恢复的时间过程。在不同斜坡上行走期间肢体运动的运动分析将用于测量这些对行为功能恢复的影响。性别和训练/激活范式的影响将单独研究。运动的这种潜在的治疗用途 解决一个重要的公共卫生问题。它技术含量低，只需要熟练从业人员的适度监督。患者可以为自己的功能恢复承担很多责任。在这项研究结束时，我们将获得支持运动功效的三个重要方面的证据，这将增加其转化前景。 公共健康相关性：拟议的研究与公共健康相关，因为美国每年有超过 100,000 例新的外伤性周围神经损伤，只有极少数受影响的个体能够完全恢复功能，并且没有针对他们的医疗（非手术）治疗。该提案中的实验预期的科学发现将代表新知识，可用于减轻这些受害者的残疾负担。