Promoting and understanding recovery of breathing after chronic spinal cord injury

项目摘要/摘要 超过50%的脊髓损伤发生在颈椎水平。在这个水平上是膈肌马达 支配横隔膜的神经元。因此，这种程度的损伤可能会导致无法呼吸。 这项拨款建议的整体目标是研究在 颈髓损伤后脊髓的膈神经环路反应及其研究和优化 可以在受伤后很长时间内恢复呼吸的疗法。通过这些研究，有效的干预措施可以 转化为相当大的脊髓损伤群体。在这份提案中，我们将利用 慢性颈髓-半横断的动物，横隔膜的一半瘫痪。在我们之前的 我们观察到酶(软骨素酶ABC)去除细胞外基质分子，称为 硫酸软骨素蛋白多糖阻止了可塑性、再生和发芽，导致了 在受伤时或接近受伤时，一度瘫痪的横隔膜的功能。已恢复 横隔膜活动有节律性和同步性。与之形成鲜明对比的是，当慢性脊髓 用软骨素酶ABC和间歇性低氧训练刺激损伤动物，混沌和 结果是无组织的活动，表明对伤害的反应发展缓慢，而且可能是不适应的。 然而，在慢性期单独使用软骨素酶可以促进正常节律和显著 增强正确构图的功能恢复。这项拨款计划的目的是：1)了解时间安排 并仔细描述发生的不适应过程；2)了解潜在的机制 这种新发现的非典型活动在慢性时间点的产生；以及3)学习如何克服 这些对伤害的负面反应使干预和康复策略可以变得更多 有效，从而导致改善功能结果。总体而言，这些研究将提供关于 适应不良的基本机制，以及可能导致健壮的功能有益的可塑性 脊髓损伤慢性期的功能性呼吸运动恢复。

PROJECT SUMMARY/ABSTRACT More than 50% of all spinal cord injuries occur at the cervical level. At this level are the phrenic motor neurons which innervate the diaphragm. Therefore, injuries at this level can lead to the inability to breathe. The overall objective of this grant proposal is to examine the changes which take place chronically in the phrenic circuitry of the cord in response to cervical spinal cord injury and investigate and optimize potential therapies that can restore breathing long after injury. Through these studies, an effective intervention can be translated to a significant population of the spinal cord injured community. In this proposal we will utilize chronic cervical spinal cord-hemisected animals which have half of the diaphragm paralyzed. In our earlier studies we observed that enzymatic (chondroitinase ABC) removal of extracellular matrix molecules, called chondroitin sulfate proteoglycans, which block plasticity, regeneration, and sprouting, led to restoration of function of the once paralyzed hemidiaphragm when administered at or near the time of injury. Recovered diaphragmatic activity was rhythmic and synchronized. In stark contrast, when the spinal cord of chronically injured animals was stimulated with chondroitinase ABC and intermittent hypoxia training, chaotic and unstructured activity resulted, suggesting slowly developing and potentially maladaptive responses to injury. However, the use of chondroitinase alone at chronic stages can promote normal rhythm and dramatically enhance properly patterned functional recovery. This grant proposal seeks to: 1) understand the time course and carefully describe the maladaptive processes that take place; 2) understand the mechanisms underlying the production of this newly discovered atypical activity at chronic time points; and 3) learn how to overcome these negative responses to injury so that interventions and rehabilitative strategies can become more effective, thereby leading to improved functional outcomes. Overall, these studies will provide insight on the basic mechanisms that underlie maladaptive, as well as functionally beneficial plasticity that can lead to robust functional respiratory motor recovery at chronic stages of spinal cord injury.