Optimizing functional recovery following cervical spinal cord injury

描述（由申请人提供）：脊髓损伤（SCI）导致许多功能的丧失，其中运动障碍无疑是最常见的神经系统预后。尤其严重的是通常发生在脊髓颈段的损伤。在这些程度上，脊髓损伤不仅影响上肢和下肢的运动，而且还损害了生存所需的一种更基本的功能——呼吸。颈椎脊髓损伤后呼吸系统并发症的发生率很高，即使不需要辅助通气也可能发生。此外，呼吸功能障碍和相关的继发性并发症仍然是颈椎脊髓损伤患者发病和死亡的主要原因。尤其令人关注的是，近年来，颈椎缺血再灌注手术的数目有所增加。尽管最佳的脊髓修复尚未实现，但越来越多的实验和临床证据表明，随着时间的推移，损伤后的一些自发功能恢复-或“可塑性”。然而，可归因于可塑性的改善程度仍然有限。我们最近的实验结果表明，在临床相关的颈椎脊髓损伤后，在损伤部位移植干细胞可以增强解剖修复和改善膈肌功能。膈肌被认为是呼吸的主要肌肉。本文提出的实验建立在我们对颈椎脊髓损伤后呼吸结果的丰富经验的基础上，并将测试成熟的供体神经细胞是否能在解剖学和功能上与负责膈肌活动的脊髓回路相结合。这些实验还将采用一种新的“光遗传学”方法来控制移植细胞的活性，并测试在供体神经元和受伤的宿主脊髓之间是否可以增强功能。这些实验不仅将在一个重要的和临床相关的损伤模型中测试一种有希望的治疗方法，而且它们将显著提高我们对广泛的神经移植方法的治疗潜力的理解，包括许多目前正在实验和临床测试的干细胞疗法。

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) results in the loss of many functions, of which motor disability is undoubtedly the more commonly recognized neurological outcome. Especially devastating are injuries that commonly occur in the cervical region of the spinal cord. At those levels SCI affects not only upper and lower extremity movements, but also impairs one of the more basic functions required for survival - namely, respiration. There is a high incidence of respiratory complications following cervical SCI, which can occur even when assisted ventilation is not required. Furthermore, respiratory dysfunction and associated secondary complications remain the leading cause of morbidity and mortality in people with cervical SCI. Particularly concerning is that the number of cervical SCIs has increased in recent years. Although optimal spinal cord repair has yet to be achieved, there is mounting experimental and clinical evidence for some spontaneous functional recovery - or "plasticity" - over time post-injury. However, the extent of improvement that can be attributed to plasticity remains limited. Results from our recent experiments have demonstrated that transplantation of stem-like cells at the site of injury can enhance anatomical repair and improve diaphragm function following clinically-relevant cervical SCI. The diaphragm is regarded as the primary muscle of respiration. The experiments proposed here build upon our extensive experience with respiratory outcomes following cervical SCI, and will test whether maturing donor nerve cells can anatomically and functionally integrate with spinal circuits responsible for diaphragm activity. These experiments will also employ a novel "optogenetic" approach to control the activity of transplanted cells and test whether the functionality can be enhanced between donor neurons and the injured host spinal cord. Not only will these experiments test a promising treatment approach in an important and clinically relevant injury model, but they will significantl improve our understanding of the therapeutic potential of a wide range of neuronal transplantation approaches, including many of the stem cell therapies currently being tested experimentally and clinically.