Spinal Cord Injury, Plasticity and Transplant Mediated Repair

描述(由申请人提供)： 我们的长期目标是开发可转化为临床的急性和慢性脊髓损伤(SCI)治疗方法。解剖学、生理学和行为学分析表明，治疗干预措施，如移植和运动(EX)，可导致脊髓的重组。我们的项目将解决移植(TP)对功能恢复的影响，以及恢复对本地和/或远程站点行动的依赖。项目1将侧重于成年大鼠脊髓损伤后移植神经限制性前体细胞(神经元和神经胶质细胞)所带来的好处。将探索干细胞IP促进神经保护、远距离轴突生长、跨病变传递信息和支持功能恢复的基本机制。项目2将使用棘化的猫来测试产生神经营养素的IP所实现的行为恢复是来自轴突再生还是局部营养效应。实验将测试损伤后移植延迟时的功能恢复情况，并将确定训练或移植后感觉和运动对腰椎运动回路(即CPG)重组的影响。项目3将使用脊髓化的大鼠来解决IP和EX介导的脊髓回路重组的机制。依赖活动的可塑性是否创造了更有利于轴突再生的环境，以及神经肌肉连接的可塑性是否与功能能力的改善有关，将被研究。行政核心将组织PPG参与者的每周会议，编写进度报告，并维持整个PPG预算。行为和生物力学核心将对脊髓损伤动物进行既定的和新颖的行为评估，以明确损伤和治疗的效果，并提供对恢复机制的见解。细胞和分子生物学核心将为移植提供干细胞和改良的成纤维细胞，并协助进行聚合酶链式反应和蛋白质分析。组织学核心将准备组织切片，用于追踪和免疫细胞化学反应，并对TP介导的轴突再生和萌发进行图像分析。外科中心将协助准备脊髓损伤动物和移植程序。我们的策略是使用多种损伤模型和治疗组合来促进修复并了解功能恢复的机制。这项计划与未来脊髓损伤治疗计划的设计和实施有直接关系。

DESCRIPTION (provided by applicant): Our long-term goal is to develop treatments for acute and chronic spinal cord injury (SCI) that can be translated into the clinic. Therapeutic interventions, such as transplantation and exercise (EX), lead to reorganization of the spinal cord, as shown by anatomical, physiological and behavioral assays. Our Projects will address transplant (TP)-mediated effects on recovery of function and the reliance of recovery on actions at local and/or distant sites. Project 1 will focus on the benefits offered by transplantation of neural restricted precursor cells (neuronal and glial) after adult rat SCI. Basic mechanisms by which stem cell IPs promote neuroprotection, long distance axonal growth, relay information across a lesion and support recovery of function will be explored. Project 2 will use spinalized cats to test whether behavioral recovery attained with neurotrophin-producing IPs results from axonal regeneration or local trophic effects. Experiments will test for recovery of function when transplantation is delayed after injury and will define sensory and motor influences on reorganization of lumbar locomotor circuits (i.e. CPG) after training or transplantation. Project 3 will use spinalized rats to address mechanisms of IP- and EX-mediated reorganization of spinal cord circuitry. Whether activity-dependent plasticity creates an environment more conducive to axonal regeneration and if plasticity of neuromuscular junctions relates to improved functional capabilities will be examined. The Administration Core will organize weekly meetings of PPG participants, prepare progress reports and maintain the entire PPG budget. The Behavior and Biomechanics Core will conduct established and novel behavioral assessments of SCI animals to specify the effects of lesions and treatments and to provide insights into recovery mechanisms. The Cell and Molecular Biology Core will provide stem cells and modified fibroblasts for transplantation and assist with PCR and protein assays. The Histology Core will prepare tissue sections for tract tracing and immunocytochemical reactions and perform image analysis of TP-mediated axonal regeneration and sprouting. The Surgery Core will assist with preparation of SCI animals and transplantation procedures. Our strategy is to employ multiple injury models and combinations of treatments to promote repair and to understand mechanisms of functional recovery. This program has direct relevance to the design and implementation of future treatment programs for SCI.