Mechanisms of intermittent hypoxia-induced motor recovery in persons with SCI

脊髓损伤患者间歇性缺氧诱导运动恢复的机制

• 批准号: 8925123
• 负责人: Randy D Trumbower
• 金额: $ 43.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925123
• 关键词: Acute; Adenosine; Brain; Brain-Derived Neurotrophic Factor; Caffeine; Chronic; Data; Dependence; Electromyography; Employee Strikes; Exposure to; Figs - dietary; Gait; Genetic Polymorphism; Genotype; Goals; Health; Human; Hypoxia; Individual; Injury; Insemination, Artificial, Homologous; Intervention; Knowledge; Learning; Left; Leg; Locomotor Recovery; Lower Extremity; Measurement; Mission; Motor; Motor Neurons; Movement; Muscle; Neural Pathways; Neuromechanics; Neuronal Plasticity; Oxygen; Pathway interactions; Performance; Persons; Property; Rattus; Recovery; Recovery of Function; Research; Research Personnel; Rodent Model; Role; Serotonin; Specificity; Spinal; Spinal Cord; Spinal Injuries; Spinal cord injury; Staging; Testing; Therapeutic; Training; Treatment Efficacy; United States National Institutes of Health; Walking; base; functional plasticity; improved; motor function improvement; motor recovery; muscle strength; novel; receptor; research study; respiratory; strength training; task analysis; tool; translational study

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) disrupts connections between the brain and spinal cord, causing devastating loss of mobility and independence. Most injuries are incomplete (iSCI), leaving intact at least some neural pathways to motor neurons that control movement. Although spontaneous plasticity in these spared pathways underlies some functional recovery, the extent of spontaneous recovery after iSCI is slow, variable and frustratingly limited. There is a critical need for new therapies that induce further improvements in persons with chronic iSCI. We recently demonstrated that repetitive exposure to acute intermittent hypoxia (rAIH), alone or in combination with walking training, stimulates motor recovery in persons with chronic iSCI. As an early stage investigator, I now propose to test four hypotheses concerning mechanisms of rAIH-induced motor recovery using multiple experimental approaches, including muscle electromyography, measurements of walking dynamics and leg strength, genotyping and pharmacological intervention. In Aim 1, we will focus on the neuromechanical bases of improved walking after rAIH, including increased motor gain (muscle activity) and coordination, as well as, reduced step-by-step variability. In Aim 2, we will test whether the functional benefits of rAIH when combined with training (strength or walking) are task-specific. We hypothesize that the cellular mechanisms that underlie the benefits of rAIH (alone or combined with training) in respiratory and non- respiratory motor function in rodent models applies also to humans with chronic, iSCI. Since AIH induces spinal motor plasticity in rats by a mechanism that requires serotonin-dependent synthesis of brain derived neurotrophic factor (BDNF), in Aim 3, we will explore the BDNF-dependence of rAIH-induced motor recovery by assessing the impact of extent of functional recovery in individuals with bdnf polymorphisms known to undermine spinal BDNF function in humans. Finally, concurrent activation of competing cellular cascades during AIH (initiated by serotonin and adenosine, respectively) undermines respiratory motor plasticity in rats. By removing the adenosine-dependent mechanism, greater functional plasticity can be achieved. Thus, in Aim 4, we hypothesize that, by pharmaceutically removing the adenosine constraint on rAIH-induced spinal plasticity via caffeine administration, the therapeutic efficacy of rAIH will improve, increasing its potential asa viable treatment to improve motor function. Each aim is supported by substantial preliminary data, suggesting that the proposed experiments will advance our understanding of mechanisms giving rise to rAIH-induced motor recovery after iSCI. An important goal guiding our research is to identify ways to optimize rAIH-induced plasticity, thereby promoting meaningful functional recovery in persons with chronic iSCI.

描述(申请人提供)：脊髓损伤(SCI)破坏大脑和脊髓之间的连接，导致严重的行动能力和独立性丧失。大多数损伤是不完全的(ISCI)，至少保留了一些通往控制运动的运动神经元的神经通路。虽然这些备用通路中的自发可塑性是某些功能恢复的基础，但ISCI后的自发恢复程度是缓慢的、可变的和令人沮丧的有限的。迫切需要新的治疗方法，以进一步改善慢性ISCI患者的病情。我们最近证明，重复暴露于急性间歇性低氧(RAIH)，单独或与步行训练相结合，可以刺激慢性ISCI患者的运动恢复。作为一名早期研究者，我现在建议使用多种实验方法来验证关于RAIH诱导的运动恢复机制的四种假说，包括肌肉肌电图、步行动力学和腿部力量的测量、基因分型和药物干预。在目标1中，我们将重点介绍RAIH后改善步行的神经力学基础，包括增加运动增益(肌肉活动)和协调性，以及减少步进式变异性。在目标2中，我们将 测试Raih与训练(力量或步行)相结合时的功能益处是否具有任务特异性。我们假设，在啮齿动物模型中，Raih(单独或联合训练)在呼吸和非呼吸运动功能方面的益处背后的细胞机制也适用于患有慢性ISCI的人类。由于AIH通过一种需要5-羟色胺依赖的脑源性神经营养因子(BDNF)合成的机制来诱导大鼠的脊髓运动可塑性，在目标3中，我们将通过评估BDNF基因多态性对人类脊髓BDNF功能损害的个体的功能恢复程度的影响，来探索RaiH诱导的运动恢复对BDNF的依赖。最后，AIH期间竞争性细胞级联的同时激活(分别由5-羟色胺和腺苷启动)破坏了大鼠的呼吸运动可塑性。通过去掉腺苷依赖机制，可以获得更大的功能可塑性。因此，在目标4中，我们假设，通过给予咖啡因从药物上消除腺苷对RAIH诱导的脊髓可塑性的限制，RAIH的治疗效果将得到改善，增加其作为改善运动功能的可行治疗的潜力。每个目标都得到了大量初步数据的支持，这表明拟议的实验将促进我们对ISCI后Raih诱导的运动恢复机制的理解。指导我们研究的一个重要目标是确定优化RAIH诱导的可塑性的方法，从而促进慢性ISCI患者有意义的功能恢复。