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）：我们最近两项关于嗅鞘胶质细胞（OEC）移植潜力的研究提供了确凿的证据，证明成年大鼠在完全脊髓横断后功能重新连接和感觉运动恢复。基于这些发现，OEC治疗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。本研究的问题是，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在幅度和特异性上得到增强。核心假设是，OEC的再生效果可以通过活动依赖机制来增强，例如硬膜外脊髓刺激（ES）结合血清素能激动剂，以及运动任务训练（攀登或台阶训练）。我们实验室的很多工作都集中在慢性低强度ES对完全瘫痪哺乳动物的影响上，尽管机制尚不清楚，ES加5 -羟色胺能激动剂喹帕嗪激活腰骶神经回路，极大地增强了脊柱大鼠的运动能力。我们最近在人体模型上的工作表明，当与运动训练相结合时，ES可以触发功能再生事件，恢复独立站立和下肢运动的意志控制。为了进一步制定策略来放大先前观察到的oec介导效应的强度，提出了两个特定目标，使用成纤维细胞和oec处理的完整脊髓横断大鼠和广泛的电生理、解剖和功能评估。具体目标1将确定OEC移植的再生效果是否比成纤维细胞对照更大，以及ES和quipazine（调节脊髓兴奋性）或“自愿”发起的攀爬任务训练（参与棘上通路）是否会促进OEC促进的轴突再生和感觉运动恢复。特异性目标2询问，通过ES和自主攀爬训练的联合治疗或ES和跑步机步训练的联合治疗，OEC移植的再生效果是否更强。我们预计，由OEC移植引发的再生的大小和特异性将通过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棘上和本体神经网络，以改善选定的感觉运动任务的表现。这些研究的创新特征包括对清醒行为的脊髓大鼠进行复杂的诱发电位测量，全面的功能评估工具，以及追踪实验来检测棘上和本体脊髓神经元的再生。这些研究的意义在于确定在多大程度上，横断部位的轴突再生量和建立的重新连接的特异性都可以通过活性依赖机制来增强。最终，这些机制可能是增强全瘫痪SCI患者OEC移植带来的功能益处的最佳候选机制之一。