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）：我们最近进行的两项关于嗅觉神经胶质细胞（OEC）移植的潜力的研究提供了完整脊髓横断后成年大鼠功能性重新连接性和感觉运动恢复的结论性证据。基于这些发现，由OEC处理诱导的轴突再生促进了一些所需的感觉运动功能，但抑制了其他感觉。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来增强大小和特异性。中心假设是，通过活动依赖性机制，例如硬膜外脊髓刺激（ES）与血清素能激动剂结合使用，以及用于运动任务（攀爬或步骤训练）的训练，可以增强OEC的再生作用。我们实验室的大量工作集中在完全瘫痪的哺乳动物中慢性，低强度ES的影响，尽管该机制仍然不清楚，但ES加上血清素能激动剂奎普嗪会激活腰椎神经电路，并大大增强了脊柱大鼠的运动。我们最近在人类模型中的工作表明，当与运动训练结合使用时，ES可以触发功能再生事件，并恢复下肢运动的独立站立和自愿控制。为了进一步制定策略以扩大先前观察到的OEC介导的效果的大小，使用成纤维细胞和OEC处理的完整脊髓跨性别大鼠和广泛的电生理，解剖学和功能评估提出了两个具体目标。具体目标1将确定OEC移植的再生效应是否大于成纤维细胞对照的再生作用，以及ES和Quipazine（调节脊柱兴奋性）是否或“自愿”对攀岩任务（以互动supraspinal Pathways的培训）的“自愿”启动培训，将促进OEC促进的轴突纤毛轴突恢复和传感器的回收。特定的目标2询问OEC移植的再生效应是否通过ES和自愿攀爬训练的联合处理或ES和跑步机步骤训练的治疗方法增强时是否更健壮。我们预计，EEC移植引发的再生的大小和特异性将通过ES和攀爬训练最大程度地增强，并且这些干预措施将刺激上脊髓和前脊髓网络，以提高所选感觉运动任务的性能。这些研究的创新特征包括对行为脊柱大鼠的诱发电位的复杂测量，全面的功能评估工具，以及追踪实验，以检测上脊髓神经元和前脊髓神经元的再生。这些研究的重要性是确定在整个横向位点之间的轴突再生量以及已建立的重新连接的特异性的程度，可以通过活动依赖性机制来增强。最终，这种机制可能是提高完全瘫痪的SCI患者OEC移植所获得的功能益处的最佳候选者之一。