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: 8766011
• 负责人: Randy D Trumbower
• 金额: $ 41.81万
• 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/8766011
• 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; 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; improved; motor function improvement; muscle strength; novel; public health relevance; 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（由申请人提供）：脊髓损伤（SCI）破坏了大脑和脊髓之间的连接，导致破坏性的丧失活动性和独立性。大多数损伤是不完全的（iSCI），至少有一些神经通路完好无损地连接到控制运动的运动神经元。虽然这些备用通路的自发可塑性是一些功能恢复的基础，但iSCI后自发恢复的程度是缓慢的、可变的和令人沮丧的有限的。迫切需要新的疗法，以诱导慢性iSCI患者的进一步改善。我们最近证明，反复暴露于急性间歇性缺氧（rAIH），单独或与步行训练相结合，刺激慢性iSCI患者的运动恢复。作为一个早期阶段的研究者，我现在建议使用多种实验方法，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来测试四个假设有关的机制rAIH诱导的运动恢复。在目标1中，我们将关注rAIH后改善行走的神经力学基础，包括增加运动增益（肌肉活动）和协调性，以及减少逐步变化。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（单独或与训练相结合）在呼吸和非呼吸运动功能方面的益处的细胞机制也适用于患有慢性iSCI的人类。由于AIH诱导大鼠脊髓运动可塑性的机制，需要依赖于脑源性神经营养因子（BDNF）的合成，在目的3中，我们将探讨BDNF依赖性rAIH诱导的运动恢复的影响，通过评估的程度，功能恢复的bdnf多态性，破坏人类脊髓BDNF功能的个人。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。通过去除腺苷依赖性机制，可以实现更大的功能可塑性。因此，在目的4中，我们假设，通过给予咖啡因，通过药物消除腺苷对rAIH诱导的脊髓可塑性的限制，rAIH的治疗效果将得到改善，增加其阿萨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。