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。脊髓局部细胞环境的感受性和损伤后的时间是两个密不可分的因素。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允许的细胞环境而有所不同。这项建议将研究这些因素的相互作用，以确定不同形式的特定任务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在中度/重度脊髓损伤后，偏心训练是否比单独进行踏步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，而上坡TM训练将消除偏心动作，并将结果与在平板跑步机(TM)上进行的传统训练进行比较。此外，我们将通过比较急性(2-9天)和迟发性脊髓损伤(35-42天)(目标2)期间的训练来确定任务特定训练的最佳治疗窗口。基质金属蛋白酶-9(MMP9)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。我们将确定基质金属蛋白酶-9是否与特定任务训练相互作用，从而影响脊髓损伤后的运动恢复(目标3)。初步证据表明，在训练中强调古怪活动是有益的，但通过上坡训练消除这种活动是非常有害的。此外，基质金属蛋白酶-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，无论是在基质金属蛋白酶-9达到峰值后进行的偏心任务特定训练，还是与早期药物阻断基质金属蛋白酶-9一起进行，都将促进脊髓损伤后最佳运动恢复。

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.