Behavioral and Cellular Determinants of Treadmill Training and Recovery after SCI

描述（由申请人提供）：脊髓损伤（SCI）后行走的最佳恢复取决于几个因素。两个不可分割的因素是脊髓中局部细胞环境的感受性和损伤后经过的时间。因此，对治疗的反应可以根据训练的类型、何时开始以及是否存在容许的细胞环境而变化。该建议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。该提案的一个创新方面将是确定离心训练是否比中度/重度SCI后单独的步行活动恢复更多的运动恢复（目标1）。我们将使用下坡跑步机（TM）训练来强调偏心动作，上坡TM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（2-9天）或晚期SCI（35-42天）期间的训练来定义任务特定训练的最佳治疗窗口（目标2）。基质金属蛋白酶-9（MMP-9）已被确定为SCI发病机制的关键介质和活动依赖性学习的重要因素。我们将确定MMP-9是否与任务特异性训练相互作用以影响SCI后的运动恢复（目的3）。初步证据表明，在训练过程中加强离心活动是有益的，但通过上坡训练消除它是非常有害的。此外，MMP-9似乎阻碍任务特异性训练和运动恢复后SCI早期。因此，我们假设，偏心任务特定的训练，交付后，峰值MMP-9或结合早期药物阻断MMP-9将促进SCI后的最佳运动恢复。

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.