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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

基本信息

批准号：
10468326
负责人：
Michael Aron Lane
金额：
$ 33.6万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468326
关键词：
Address Adult Anatomy Animals Astrocytes Axon 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)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 Persons 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 Transplant Recipients Transplantation Treatment Efficacy Work anatomical tracing awake axon growth axon guidance base cellular engineering 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

项目摘要

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.

呼吸受损是颈脊髓损伤 (SCI) 的毁灭性后果，代表着严重的后果。受伤人员的负担并增加死亡风险。呼吸功能障碍及相关继发性并发症仍然是颈椎 SCI 患者发病和死亡的主要原因。特别令人担忧的是，有报告表明，近年来宫颈脊髓损伤的数量有所增加。虽然有越来越多的临床和实验证据表明呼吸自发改善、恢复程度 – 或功能可塑性 – 仍然不完整。然而，可塑性依赖于在不完全性脊髓损伤（SCI）。因此，在没有治疗干预和解剖学的情况下恢复的程度修复有限。为了解决这一限制，并增强呼吸的可塑性和恢复性颈椎 SCI，拟议的工作旨在使用新型细胞疗法促进膈运动修复控制膈肌功能的通路——膈肌是呼吸所必需的呼吸肌。我们最近的实验研究结果表明，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修复并改善呼吸功能继SCI。移植的神经前体细胞存活、增殖并与受伤的宿主整合脊髓，有助于修复呼吸通路。这里提出的实验建立在我们的基础上在膈运动系统方面拥有丰富的经验，以测试移植精制的新策略与膈功能相关的神经元间前体。使用临床相关的挫伤模型颈椎脊髓损伤，我们将测试移植的神经祖细胞是否能够在解剖学和功能上整合通过这个膈系统，促进膈肌持续、持久的恢复。这些实验不仅将测试一种创新且有前途的治疗方法，而且还将显着提高了我们对各种神经元治疗潜力的理解移植方法，包括目前正在测试的许多干细胞疗法实验和临床上。