Optimizing functional recovery following cervical spinal cord injury

描述（由申请人提供）：脊髓损伤（SCI）导致许多功能丧失，其中运动残疾无疑是更常见的神经学结局。尤其是破坏性的是通常发生在脊髓颈部的损伤。在这些水平上，SCI不仅影响上肢和下肢的运动，而且还损害了生存所需的更基本的功能之一，即呼吸。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会发生。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率和死亡率的主要原因。尤其令人担忧的是，近年来宫颈SCI的数量有所增加。虽然最佳的脊髓修复尚未实现，但有越来越多的实验和临床证据表明，随着时间的推移，损伤后会出现一些自发的功能恢复-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，在损伤部位移植干细胞样细胞可以增强临床相关的颈脊髓损伤后的解剖修复和改善膈肌功能。膈肌被认为是呼吸的主要肌肉。这里提出的实验建立在我们对颈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可以在解剖学上和功能上与负责横膈膜活动的脊髓回路整合。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，并测试供体神经元和受损宿主脊髓之间的功能是否可以增强。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前途的治疗方法，而且它们将显著提高我们对广泛的神经元移植方法的治疗潜力的理解，包括目前正在实验和临床上测试的许多干细胞疗法。 公共卫生相关性：虽然长期以来人们一直认为脊髓损伤会导致永久性瘫痪，但研究表明，当受伤的脊髓试图重建自己时，会自然发生少量的恢复-称为可塑性。虽然恢复的程度是有限的，但加强这种可塑性的治疗可能会导致bst的治疗结果。因此，本研究计划将测试移植健康神经元是否可以提供构建模块，以形成能够增强可塑性和改善恢复的新神经元通路。

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. PUBLIC HEALTH RELEVANCE: While it has long been thought that spinal cord injuries resulted in permanent paralysis, research has shown that a small amount of recovery - called plasticity - can occur naturally as the injured spinal cord attempts to rebuild itself. Although th extent of recovery is limited, treatments that strengthen this plasticity will likely lead to the bst therapeutic outcomes. Accordingly, the present research program will test whether transplanting healthy neurons can provide the building blocks to form new neuronal pathways capable of enhancing plasticity and improve recovery.