Activity-dependent functional regeneration after SCI and OEC transplantation

SCI 和 OEC 移植后活动依赖性功能再生

• 批准号: 8869049
• 负责人: REGGIE EDGERTON
• 金额: $ 48.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869049
• 关键词: Address; Adult; Axon; Behavior assessment; Brain; Brain Stem; Cell Transplantation; Cell Transplants; Chest; Chronic; Combined Modality Therapy; Contralateral; Educational Intervention; Electric Stimulation; Evaluation; Event; Evoked Potentials; Fibroblasts; Hindlimb; Human; Implant; Individual; Intervention; Joints; Laboratories; Learning; Leg; Locomotion; Lower Extremity; Mammals; Measurement; Mediating; Modeling; Motor; Motor Evoked Potentials; Motor Neurons; Mus; Natural regeneration; Neuroglia; Neurons; Neurostimulation procedures of spinal cord tissue; Paralysed; Pathway interactions; Performance; Physiological; Public Health; Quipazine; Rattus; Recovery; Reporting; Rewards; Rodent; Sensorimotor functions; Serotonin Agonists; Site; Specificity; Spinal; Spinal Cord; Spinal Cord transection injury; Spinal cord injury; Spinal cord injury patients; Step training; Tracer; Training; Transplantation; Weight-Bearing state; Work; awake; axon regeneration; base; effective therapy; functional outcomes; improved; innovation; limb movement; motor function recovery; motor recovery; neural circuit; neuroregulation; novel; regenerative; repaired; research study; tool

DESCRIPTION (provided by applicant): Our two recent studies on the potential of olfactory ensheathing glial cell (OEC) transplantation provide conclusive evidence of functional re-connectivity and sensorimotor recovery in adult rats after a complete spinal cord transection. Based on these findings, the axon regeneration induced by OEC treatment facilitated some desired sensorimotor functions, but suppressed others. This proposal asks if the OEC effect on hindlimb motor function can be enhanced in both magnitude and specificity with different activity- based interventions. The central hypothesis is that the regenerative effects of OEC can be enhanced by activity-dependent mechanisms, such as epidural spinal cord stimulation (ES) combined with a serotonergic agonist, and training for a motor task (climbing or step training). Much work from our laboratory has focused on the effects of chronic, low intensity ES in completely paralyzed mammals, and although the mechanism is still unclear, ES plus the serotonergic agonist quipazine activates the lumbosacral neural circuitry and greatly enhances locomotion in spinal rats. Our recent work in a human model shows that ES, when combined with motor training, can trigger functional regenerative events and recovery of independent standing and volitional control of lower limb movements. To further develop strategies to amplify the magnitude of the OEC-mediated effects observed previously, two Specific Aims are proposed using fibroblast- and OEC-treated complete spinal cord transected rats and extensive electrophysiological, anatomical, and functional assessments. Specific Aim 1 will determine whether the regenerative effects of OEC transplantation are greater than those of the fibroblast controls, and if ES and quipazine (to modulate spinal excitability) or a "voluntarily" initiated training of a climbing task (to engage supraspinal pathways) will promote OEC-facilitated axonal regeneration and sensorimotor recovery. Specific Aim 2 asks if the regenerative effects of OEC transplantation are more robust when enhanced by the combined treatments of ES and voluntary climb training or the treatments of ES and treadmill step training. We anticipate that both the magnitude and specificity of the regeneration initiated by OEC transplantation will be most enhanced by ES and climb training, and that these interventions will stimulate the supraspinal and propriospinal networks to improve performance of selected sensorimotor tasks. Innovative features of these studies include the sophisticated measurements of evoked potentials in awake behaving spinal rats, a comprehensive battery of functional evaluation tools, and tracing experiments to detect regeneration of supraspinal and propriospinal neurons. The significance of these studies is to determine the extent to which both the amount of axon regeneration across the transection site and the specificity of the established re-connections can be enhanced by activity-dependent mechanisms. Ultimately, such mechanisms may be among the best candidates to enhance the functional benefits derived from OEC transplantation in completely paralyzed SCI patients.

描述（由申请人提供）：我们最近的两项关于嗅鞘神经胶质细胞（OEC）移植潜力的研究提供了脊髓完全横断后成年大鼠功能重新连接和感觉运动恢复的确凿证据。基于这些发现，OEC处理诱导的轴突再生促进了一些期望的感觉运动功能，但抑制了其他功能。该建议询问OEC对后肢运动功能的影响是否可以通过不同的基于活动的干预措施在幅度和特异性上得到增强。中心假设是OEC的再生作用可以通过活动依赖性机制增强，例如硬膜外脊髓刺激（ES）与多巴胺能激动剂的组合，以及运动任务的训练（攀爬或台阶训练）。我们实验室的许多工作都集中在慢性低强度ES对完全瘫痪的哺乳动物的影响上，尽管其机制尚不清楚，但ES加上多巴胺能激动剂奎帕嗪激活了腰骶神经回路，大大增强了脊髓大鼠的运动能力。我们最近在人体模型中的工作表明，ES与运动训练相结合时，可以触发功能性再生事件，恢复独立站立和下肢运动的意志控制。为了进一步开发策略以放大先前观察到的OEC介导的效应的幅度，提出了两个特定目的，使用成纤维细胞和OEC处理的完全脊髓横断大鼠和广泛的电生理学、解剖学和功能评估。具体目标1将确定OEC移植的再生效果是否大于成纤维细胞对照，以及ES和喹帕嗪（调节脊髓兴奋性）或“自愿”开始的攀爬任务训练（参与脊髓上通路）是否会促进OEC促进的轴突再生和感觉运动恢复。具体目标2询问当通过ES和自愿攀爬训练的组合治疗或ES和跑步机台阶训练的治疗增强时，OEC移植的再生效果是否更稳健。我们预计，由OEC移植启动的再生的幅度和特异性将通过ES和攀爬训练得到最大程度的增强，并且这些干预措施将刺激脊髓上和脊髓本体网络，以提高选定的感觉运动任务的性能。这些研究的创新特征包括清醒行为脊髓大鼠的诱发电位的复杂测量，功能评估工具的全面电池，以及检测脊髓上和脊髓本体神经元再生的追踪实验。这些研究的意义是确定在何种程度上可以通过活性依赖性机制增强横断部位的轴突再生量和已建立的重新连接的特异性。最终，这种机制可能是最好的候选人之一，以提高来自OEC移植在完全瘫痪的SCI患者的功能的好处。