Optimizing functional recovery following cervical spinal cord injury

优化颈脊髓损伤后的功能恢复

• 批准号: 8718123
• 负责人: Michael Aron Lane
• 金额: $ 32.27万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718123
• 关键词: Adult; Affect; Animals; Axon; Behavior; Cations; Cell Transplants; Cells; Cervical; Cervical spinal cord injury; Chronic; Clinical; Contusions; Coupled; Development; Electrodes; Environmental air flow; Fiber; Functional disorder; Goals; Hour; Implant; Incidence; Injury; Interneurons; Lead; Light; Lower Extremity; Measures; Methods; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Movement; Muscle; Neurological outcome; Neurons; Neurotransmitters; Outcome; Output; Paralysed; Pathway interactions; Phenotype; Phrenic Motor System; Plethysmography; Population; Principal Investigator; Procedures; Rattus; Recovery; Recovery of Function; Relative (related person); Research; Respiration; Respiratory Diaphragm; Rhodopsin; Side; Site; Spinal; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Structure of phrenic nerve; Suspension substance; Suspensions; Synapses; System; Technology; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Transplantation; Upper Extremity; Viral; axon growth; clinically relevant; disability; experience; fetal; functional improvement; immunocytochemistry; improved; indexing; injured; mortality; novel; optogenetics; progenitor; programs; relating to nervous system; repaired; research study; respiratory; spinal cord repair; stem; stem cell therapy; therapeutic target

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.

描述（申请人提供）：脊髓损伤（SCI）会导致许多功能丧失，其中运动障碍无疑是更普遍认可的神经系统后果。尤其具有破坏性的是通常发生在脊髓颈部的损伤。在这些水平上，脊髓损伤不仅影响上肢和下肢的运动，而且还会损害生存所需的一项更基本的功能——即呼吸。颈椎 SCI 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并发症仍然是颈椎 SCI 患者发病和死亡的主要原因。尤其令人担忧的是，近年来宫颈脊髓损伤的数量有所增加。尽管最佳脊髓修复尚未实现，但越来越多的实验和临床证据表明，随着时间的推移，损伤后会出现一些自发功能恢复（或“可塑性”）。然而，可塑性带来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 SCI 后，在损伤部位移植干细胞样细胞可以增强解剖修复并改善膈肌功能。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椎 SCI 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和功能上与负责膈肌活动的脊髓回路整合。这些实验还将采用一种新颖的“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。这些实验不仅将在重要且与临床相关的损伤模型中测试一种有前途的治疗方法，而且将显着提高我们对各种神经元移植方法（包括目前正在实验测试的许多干细胞疗法）的治疗潜力的理解和临床上。