Exercise, Intraspinal Transplants and Spinal Cord Plasticity

运动、椎管内移植和脊髓可塑性

• 批准号: 8652510
• 负责人: John D. Houle
• 金额: $ 25.26万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8652510
• 关键词: Acute; Address; Adult; Affect; Afferent Neurons; Animal Model; Animals; Area; Axon; Back; Behavior; Behavioral; Brain-Derived Neurotrophic Factor; Chest; Chondroitinases; Chronic; Control Animal; Cues; Digestion; Distal; Electrophysiology (science); Exercise; Felis catus; Fibroblasts; Future; Growth; H-Reflex; Hindlimb; Hyaluronidase; Individual; Injury; Instruction; Label; Length; Lesion; Lumbar spinal cord structure; Mediating; Mental Depression; Methods; MicroRNAs; Modeling; Motor; Motor Neurons; Muscle; NTF3 gene; Natural regeneration; Neurons; Operative Surgical Procedures; Patients; Perception; Peripheral Nerves; Preparation; Procedures; Process; Proteins; Proteoglycan; Rattus; Recovery; Recovery of Function; Sensory; Site; Source; Spinal; Spinal Cord; Spinal Cord Plasticity; Spinal cord injury; Staging; Step training; Synapses; Testing; Thoracic spinal cord structure; Time; Training; Translations; Transplantation; Up-Regulation; axon growth; axon regeneration; base; design; efficacy testing; functional improvement; improved; injured; kinematics; mRNA Expression; neurotrophic factor; pre-clinical; protein expression; receptor; regenerative; repaired; research study; response; restoration; spinal pathway; spinal reflex; success; treadmill training; treatment strategy; true blue

Experimental spinal cord injury (SCI) models have helped define levels of structural and functional plasticity within the spinal cord and affected muscles. Peripheral nerve grafts (PNGs) support the regeneration of acute and chronically injured neurons although growth beyond the graft, back into the spinal cord, is limited in terms of the number and length of axonal extension. Digestion of inhibitory proteoglycans with Chondroitinase is partially effective in increasing axonal outgrowth and there is evidence of functional synaptic connection between regenerated axons and spinal cord neurons. Exercise-induced increase of neurotrophic factors in thoracic and lumbar spinal cord is correlated with the restoration of motoneuron excitability (spinal reflexes) to near normal activity. Despite these successes there remain thousands of injured neurons that are not involved in reorganization and repair of the injured spinal cord. Our objectives are to address mechanistic questions related to the potential for exercise to provide trophic factor cues to potentially promote the regenerative response of injured neurons and/or to activate spinal networks to facilitate receptivity of regenerating axons. Aim 1 will address the hypothesis that exercise will promote regeneration of acute and/or chronically injured axons into a PNG, using an adult rat lower thoracic level transection injury, separate PNGs to support growth of descending vs. ascending axons and treadmill step training. Tract tracing methods will define the regenerative effort of motor and sensory neurons. Aim 2 will test whether exercise increases axonal outgrowth from a PNG and determine possible functional improve- ment related to regenerated axons by performing sensorimotor behavior, kinematic and electrophysiological analyses. In separate groups we will test whether activity-dependent plasticity is achieved with either/or an acute or delayed treatment approach. To advance the preclinical translation of our treatment strategy, results from SCI rats will be applied to a spinalized cat preparation to test whether exercise and transplantation promote regeneration-based functional recovery in a large animal model. Overall, these experiments will provide fundamental information about cellular and functional aspects of spinal cord reorganization in acute and chronic stages of SCI that will be instrumental in designing strategies for repair.

实验性脊髓损伤（SCI）模型有助于定义结构可塑性的水平 在脊髓内并影响肌肉。外围神经移植（PNGS）支持再生 急性和长期受伤的神经元尽管生长超出了移植物，但恢复到脊髓，但受到限制 就轴突扩展的数量和长度而言。消化抑制性蛋白聚糖 软骨素酶在增加轴突生长方面有效有效，并且有功能的证据 再生轴突和脊髓神经元之间的突触连接。运动引起的增加 胸腔和腰脊髓中的神经营养因子与恢复运动神经元有关 兴奋性（脊柱反射）至接近正常活动。尽管取得了这些成功，还有数千个 不参与重组和修复受伤的脊髓的受伤神经元。我们的目标 解决与锻炼潜力提供营养因素线索有关的机械问题 有可能促进受伤神经元和/或激活脊柱网络的再生反应 促进再生轴突的接受度。目标1将解决练习将促进的假设 使用成年大鼠下胸腔水平，将急性和/或长期受伤的轴突再生为PNG 横断损伤，单独的PNG，以支持下降与上升轴突的生长和跑步机步骤 训练。道追踪方法将定义运动和感觉神经元的再生努力。 AIM 2意志 测试运动是否增加了PNG的轴突生长，并确定可能的功能改善 - 通过执行感觉运动行为，运动学和电生理学，与再生轴突有关 分析。在单独的组中，我们将测试是否依赖于活动的可塑性。 急性或延迟治疗方法。为了推进我们治疗策略的临床前翻译，结果 从科学大鼠中将应用于脊柱化的猫制剂，以测试运动和移植是否 在大型动物模型中促进基于再生的功能恢复。总体而言，这些实验将 提供有关急性脊髓重组的细胞和功能方面的基本信息 SCI的慢性阶段将有助于设计维修策略。