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) 模型有助于确定结构和功能可塑性水平 在脊髓和受影响的肌肉内。周围神经移植物（PNG）支持再生 急性和慢性损伤的神经元，尽管移植物之外、返回脊髓的生长受到限制 就轴突延伸的数量和长度而言。抑制性蛋白多糖的消化 软骨素酶在增加轴突生长方面部分有效，并且有证据表明其具有功能性 再生轴突和脊髓神经元之间的突触连接。运动引起的增加 胸腰段脊髓神经营养因子与运动神经元恢复相关 兴奋性（脊髓反射）接近正常活动。尽管取得了这些成功，但仍有数以千计的人 不参与受损脊髓重组和修复的受损神经元。我们的目标 旨在解决与运动潜力相关的机械问题，以提供营养因子线索 可能促进受损神经元的再生反应和/或激活脊髓网络 促进再生轴突的接受性。目标 1 将提出这样的假设：锻炼会促进 使用成年大鼠下胸部水平将急性和/或慢性损伤的轴突再生为 PNG 横断损伤，单独的 PNG 来支持下降轴突和上升轴突的生长以及跑步机步 训练。纤维束追踪方法将定义运动和感觉神经元的再生能力。目标2将 测试运动是否会增加 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、运动学和电生理学来与再生轴突相关 分析。在不同的组中，我们将测试是否通过以下任一/或一个方法实现了活动依赖性可塑性： 急性或延迟治疗方法。为了推进我们的治疗策略、结果的临床前转化 将来自 SCI 大鼠的脊髓移植到猫制剂中，以测试运动和移植是否有效 促进大型动物模型中基于再生的功能恢复。总的来说，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修复策略。