Behavioral and Cellular Determinants of Treadmill Training and Recovery after SCI

描述（由申请人提供）：脊髓损伤（SCI）后步行的最佳恢复取决于几个因素。两个因素不可避免地交织在一起，即脊髓局部细胞环境的接受性和损伤后的时间。因此，对治疗的反应取决于训练的类型、何时开始以及是否存在一个允许的细胞环境。本提案将研究这些因素的相互作用，以确定不同形式的任务特定训练的最佳治疗窗口和细胞环境。该建议的一个创新方面是确定在中度/重度脊髓损伤后，偏心训练是否比单纯的步行活动更能恢复运动能力（目的1）。我们将使用下坡跑步机（TM）训练来强调偏心动作，使用上坡跑步机训练来消除偏心动作，并将结果与传统的平板跑步机（TM）训练进行比较。此外，我们将通过比较急性期（2-9天）或脊髓损伤晚期（35-42天）的训练来确定特定任务训练的最佳治疗窗口（目标2）。基质金属蛋白酶-9 （matrix metalloproteinase-9, MMP-9）已被认为是脊髓损伤发病的关键介质，也是活动依赖学习的重要因素。我们将确定MMP-9是否与任务特异性训练相互作用，影响脊髓损伤后的运动恢复（目的3）。初步证据表明，在训练中加强古怪的活动是有益的，但通过上坡训练消除它是相当有害的。此外，MMP-9似乎阻碍了脊髓损伤后早期的任务特异性训练和运动恢复。因此，我们假设，在MMP-9达到峰值后进行偏心任务特异性训练，或与早期药物阻断MMP-9相结合，将促进脊髓损伤后运动功能的最佳恢复。

DESCRIPTION (provided by applicant): Optimal recovery of walking after spinal cord injury (SCI) depends on several factors. Two factors inextricably entwined are the receptivity of the local cellular environment in the spinal cord and the time elapsed since injury. Thus, response to treatment can vary depending on the type of training, when it is initiated and whether a permissive cellular environment exists. This proposal will examine the interaction of these factors to determine the optimal therapeutic window and cellular environment for different forms of task specific training. An innovative aspect of the proposal will be to determine whether eccentric training restores more locomotor recovery than stepping activity alone after moderate/severe SCI (Aim 1). We will use downhill treadmill (TM) training to accentuate eccentric action and uphill TM training to eliminate it and compare outcomes to traditional training on a flat treadmill (TM). Additionally, we will define the optimal therapeutic window for task specific training by comparing training during acute (2-9 days) or late SCI (35-42 days) (Aim 2). The matrix metalloproteinase-9 (MMP-9) has been identified as a key mediator of SCI pathogenesis and an important factor in activity-dependent learning. We will determine whether MMP-9 interacts with task specific training to affect locomotor recovery after SCI (Aim 3). Preliminary evidence suggests that accentuating eccentric activity during training is beneficial but eliminating it via uphill training is quite detrimental. Also, MMP-9 seems to impede task specific training and locomotor recovery early after SCI. Therefore, we hypothesize that eccentric task specific training, delivered either after peak MMP-9 or in conjunction with early pharmacological blockade of MMP-9 will promote optimal locomotor recovery after SCI.