Neural transplants to promote respiratory plasticity after spinal cord injury

神经移植促进脊髓损伤后呼吸可塑性

• 批准号: 10238115
• 负责人: Michael Aron Lane
• 金额: $ 33.61万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238115
• 关键词: Address; Adult; Anatomy; Animals; Astrocytes; Behavior; Brain-Derived Neurotrophic Factor; Breathing; Cell Survival; Cell Therapy; Cell Transplantation; Cells; Cervical; Cervical spinal cord injury; Chronic; Clinical; Contusions; Cues; Data; Electrodes; Electrophysiology (science); Genes; Glutamates; Goals; Growth; Heterogeneity; Hypoxia; Impairment; Implant; Injury; Interneurons; Ipsilateral; Maps; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Motor Pathways; Muscle; Neuroglia; Neuronal Plasticity; Neurons; Oligodendroglia; Paralysed; Pathway interactions; Pattern; Phenotype; Phrenic Motor System; Plethysmography; Population; Population Heterogeneity; Proliferating; Rattus; Recovery; Regenerative capacity; Reporting; Research; Respiration; Respiration Disorders; Respiratory Diaphragm; Respiratory Muscles; Respiratory physiology; Site; Source; Spinal; Spinal Cord; Spinal cord injury; Stem cell transplant; Supporting Cell; Synapses; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; Transplantation; Treatment Efficacy; Work; anatomical tracing; awake; axon growth; axon guidance; base; clinically relevant; designer receptors exclusively activated by designer drugs; experience; experimental study; functional plasticity; gene therapy; improved; improved functioning; improved outcome; injured; innovation; mortality; mortality risk; motor recovery; nerve stem cell; novel; novel strategies; post-transplant; progenitor; programs; receptor; relating to nervous system; repaired; respiratory; stem cell therapy; synaptic pruning; therapeutic target; therapy outcome; ventilation

Impaired breathing is a devastating consequence of cervical spinal cord injury (SCI), representing a significant burden to injured people and increasing the risk of mortality. Respiratory dysfunction and associated secondary complications remain the leading cause of morbidity and mortality in people with cervical SCI. Particularly concerning are reports indicating that the number of cervical SCIs has increased in recent years. While there is mounting clinical and experimental evidence for spontaneous improvements in respiration, the extent of recovery – or functional plasticity – remains incomplete. However, plasticity is reliant on spared neural substrates after incomplete spinal cord injury (SCI). Thus, the extent of recovery without therapeutic intervention and anatomical repair is limited. To address this limitation, and amplify plasticity and recovery of breathing following cervical SCI, the proposed work aims to use a novel cell therapy to promote repair of phrenic motor pathways that control function of the diaphragm – a respiratory muscle essential to breathing. Results from our recent experimental studies have demonstrated that transplantation of interneuron-rich neural progenitor cells at the site of injury can promote anatomical repair and improve respiratory function following SCI. Transplanted neural precursor cells survive, proliferate and become integrated with injured host spinal cord, contributing to repair of respiratory pathways. The experiments proposed here build upon our extensive experience with the phrenic motor system, to test a novel strategy for transplanting refined interneuronal precursors that are associated with phrenic function. Using a clinically relevant contusion model of cervical SCI, we will test whether transplanted neural progenitors can anatomically and functionally integrate with this phrenic system, and promote consistent, lasting recovery of diaphragm. Not only will these experiments test an innovative and promising treatment approach, but they will significantly 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.

呼吸受损是宫颈脊髓损伤（SCI）的毁灭性结果，代表着重要的 负担受伤的人并增加死亡率的风险。呼吸功能障碍和相关次要 并发症仍然是宫颈科学患者发病和死亡率的主要原因。特别 关于报告表明近年来宫颈SCI的数量有所增加。而有 安装临床和实验证据，以提高呼吸的提高，恢复程度 - 或功能可塑性 - 仍然不完整。但是，可塑性依赖于保存的神经底物 不完全的脊髓损伤（SCI）。这是没有治疗干预和解剖学的恢复程度 维修是有限的。解决此限制，并扩大呼吸的可塑性和恢复 宫颈科学，拟议的工作旨在使用新型的细胞疗法来促进修复Phrenic Motor 控制隔膜功能的途径 - 呼吸肌肉对呼吸必不可少的途径。 我们最近的实验研究的结果表明，富含中间神经元的移植 损伤部位的神经祖细胞可以促进解剖学修复并改善呼吸功能 跟随科学。移植的神经元前体细胞生存，增殖并与受伤的宿主整合 脊髓，有助于修复呼吸道途径。这里提出的实验建立在我们的 在Phrenial Motor系统方面的丰富经验，以测试一种新的移植精制策略 与伪功能相关的神经元前体。使用临床相关的挫伤模型 宫颈科学，我们将测试移植的神经祖细胞是否可以解剖和功能整合 使用这种伪造的系统，并促进隔膜的持久恢复。 这些实验不仅会测试一种创新和有希望的治疗方法，而且还会 显着提高我们对广泛神经元治疗潜力的理解 移植方法，包括当前正在测试的许多干细胞疗法 实验和临床。