Repetitive Acute Intermittent Hypoxia for Spinal Cord Repair

重复急性间歇性缺氧用于脊髓修复

• 批准号: 10599946
• 负责人: Martin Oudega
• 金额: --
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599946
• 关键词: Acute; Adult; Agonist; Amyotrophic Lateral Sclerosis; Anatomy; Animals; Bilateral; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Contusions; Corticospinal Tracts; Cycloserine; Data; Development; Dose; Electrophysiology (science); Exposure to; Forelimb; Frequencies; Goals; Growth Associated Protein 43; Hand; Hand functions; Human; Hypoxia; Imaging Techniques; Impairment; Individual; Intervention; Knowledge; Lesion; Life; Location; Lower Extremity; Measurement; Mediating; Modeling; Motor; Motor Neurons; Multiple Sclerosis; Muscle function; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuronal Plasticity; Neurons; Patients; Persons; Pharmaceutical Preparations; Protocols documentation; Quality of life; Rattus; Recovery; Recovery Support; Recovery of Function; Research; Spinal Cord Contusions; Spinal Injuries; Spinal cord damage; Synapses; Synaptic plasticity; Testing; Training; Upper Extremity; Upper limb movement; Veterans; Work; arm function; clinical application; experimental study; grasp; hand rehabilitation; immunocytochemistry; improved; minimally invasive; motor disorder; motor function recovery; motor recovery; novel strategies; post stroke; spinal cord repair

Our overall goal is to develop effective, clinically applicable, approaches to restore upper limb function (reach- and-grasp) after chronic contusive cervical spinal cord injury (cSCI). Impairments in upper limb function significantly reduce the quality of life for people with cSCI. Reach-and-grasp actions in animals and humans are largely controlled by the corticospinal tract (CST). We argue that promoting plasticity within the CST may support the recovery of upper limb function after cSCI. Repetitive exposure to acute intermittent hypoxia (rAIH) combined with motor training is a safe, minimally invasive, treatment that elicits neuroplasticity resulting in improved recovery after cSCI, but its overall effects remain limited. Our main goals are to: 1) enhance rAIH/training-induced aftereffects on forelimb function and increase our understanding of the neuronal substrates in an adult rat model of chronic contusive cSCI, and 2) use this knowledge to guide the development of more effective rAIH/training approaches to improve upper limb function in humans with chronic contusive cSCI. In Specific Aim 1, using an adult rat model of chronic contusive cSCI, we will investigate the effects of rAIH frequency and dose on rAIH/training-mediated functional recovery of the impaired forelimb. Also, we will combine rAIH/training with NMDA-mediated synaptic plasticity through D-cycloserine treatment and study the effects on recovery of forelimb function. Immunocytochemistry with imaging techniques will be used to assess structural neuronal plasticity in the CST after rAIH/training. In Specific Aim 2, in people with chronic incomplete cSCI, guided by the findings in Specific Aim 1, we will study the effects of rAIH frequency and concurrent D-cycloserine treatment on rAIH/training-mediated upper limb function recovery. We will comprehensively analyze the effects of rAIH on the strength of electrophysiological and functional aftereffects in the upper limb. The proposed research will provide new knowledge on rAIH/training-mediated functional and anatomical aftereffects (Specific Aim 1), which will be used to develop effective rAIH/training protocols for people with contusive, functionally incomplete, cSCI (Specific Aim 2). The data from our experiments may lead to clinically applicable approaches that improve arm and hand function recovery after chronic contusive cSCI, which would positively impact the quality of life of our Veterans with cSCI. The relevance of this proposal is emphasized by the limited efficacy of current strategies to improve upper limb function after cSCI.

我们的总体目标是开发有效的、临床适用的方法来恢复上肢功能（达到- 慢性挫伤性颈脊髓损伤（cSCI）后。上肢功能障碍 显着降低 cSCI 患者的生活质量。动物和人类的伸手抓握动作 很大程度上由皮质脊髓束（CST）控制。我们认为，促进 CST 内部的可塑性可能会支持 cSCI后上肢功能的恢复。反复暴露于急性间歇性缺氧 (rAIH) 组合 运动训练是一种安全、微创的治疗方法，可引起神经可塑性，从而改善 cSCI 后有所恢复，但其总体影响仍然有限。我们的主要目标是：1) 增强 rAIH/训练引起的 对前肢功能的后遗症并增加我们对成年大鼠模型中神经元基质的理解 慢性挫伤性 cSCI，以及 2) 利用这些知识来指导更有效的 rAIH/培训的开发 改善慢性挫伤性 cSCI 患者上肢功能的方法。 在具体目标 1 中，我们将使用慢性挫伤性 cSCI 成年大鼠模型来研究 rAIH 的影响 频率和剂量对 rAIH/训练介导的受损前肢功能恢复的影响。另外，我们还将结合 rAIH/通过 D-环丝氨酸治疗进行 NMDA 介导的突触可塑性训练并研究其效果 前肢功能恢复。免疫细胞化学和成像技术将用于评估结构 rAIH/训练后 CST 中的神经元可塑性。在具体目标 2 中，在慢性不完全性 cSCI 患者中， 在具体目标 1 的研究结果的指导下，我们将研究 rAIH 频率和并发 D-环丝氨酸的影响 rAIH 治疗/训练介导的上肢功能恢复。我们将综合分析效果 rAIH 对上肢电生理和功能后遗症强度的影响。 拟议的研究将提供有关 rAIH/训练介导的功能和解剖学的新知识 后遗症（具体目标 1），将用于为患有以下疾病的人制定有效的 rAIH/培训方案 挫伤、功能不完整、cSCI（具体目标 2）。我们的实验数据可能会导致临床 改善慢性挫伤性 cSCI 后手臂和手功能恢复的适用方法，这将 通过 cSCI 对退伍军人的生活质量产生积极影响。强调了该提案的相关性 目前改善 cSCI 后上肢功能的策略效果有限。