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: 10359087
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359087
• 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; Lead; 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; base; 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（接触到 - 慢性宫颈脊髓损伤（CSCI）之后）。上肢功能的障碍 大大降低了CSCI患者的生活质量。动物和人类中的触及抓紧动作是 在很大程度上由皮质脊髓道（CST）控制。我们认为促进CST内的可塑性可能支持 CSCI后上肢功能的恢复。重复暴露于急性间歇性缺氧（RAIH）合并 借助运动训练是一种安全的，微创的治疗，引起神经可塑性，从而改善 CSCI后的恢复，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 前肢功能的后果并增加了我们对成人大鼠模型中神经元底物的理解 慢性CONCSI的CSCI，以及2）使用此知识来指导开发更有效的RAIH/培训 通过慢性CONCSI CSCI改善人类上肢功能的方法。 在特定的目标1中，使用成人大鼠的慢性CONCSI CSCI模型，我们将研究RAIH的影响 raiH/训练介导的频率和剂量的功能恢复的前肢受损的功能恢复。另外，我们将结合 通过NMDA介导的突触可塑性的RAIH/训练通过D-胞丝烯处理，并研究了对 恢复前肢功能。成像技术的免疫细胞化学将用于评估结构 RAIH/训练后CST中的神经元可塑性。在特定的目标2中，在患有慢性CSCI的患者中， 在特定目标1中的发现的指导下，我们将研究raiH频率和并发d-cycloserine的影响 RAIH/训练介导的上肢功能恢复的治疗。我们将全面分析效果 RaiH关于上肢电生理和功能后效应的强度。 拟议的研究将提供有关RAIH/培训介导的功能和解剖学的新知识 后效效期（特定目标1），该效果将用于为患有患者的患者制定有效的RAIH/培训方案 CSCI（特定AIM 2），功能不完整，功能不完整。我们实验的数据可能导致临床 适用的方法，可以改善慢性CONTUSE CSCI之后的手臂和手部功能恢复，这将 用CSCI积极影响退伍军人的生活质量。该提议的相关性由 当前策略在CSCI后改善上肢功能的有限效力。