Constructing a growth-promoting pathway for functional regeneration after SCI

构建SCI后功能再生的促生长途径

• 批准号: 9563764
• 负责人: KATHRYN Jane JONES
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9563764
• 关键词: Affect; Architecture; Atrophic; Axon; Behavior; Cell Line; Chest; Clinic; Contusions; Data; Dendrites; Dependovirus; Electrophysiology (science); Gene Expression; Gene Transfer; Goals; Growth; Growth Factor; Hindlimb; Impairment; Injury; Label; Lasers; Lesion; Locomotor Recovery; Mediating; Medical; Microdissection; Military Personnel; Modeling; Molecular Profiling; Motor; Motor Neurons; Motor Pathways; Motor output; Muscle; Muscular Atrophy; Natural regeneration; Nature; Nerve Fibers; Neurons; Neurotrophin 3; Pathway interactions; Patients; Rattus; Recovery; Recovery of Function; Research; Schwann Cells; Serotyping; Signal Pathway; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Synapses; Synaptic Transmission; System; Techniques; Tetanus Helper Peptide; Thoracic spinal cord structure; Translating; Transplantation; Veterans; Viral Vector; axon growth; axon regeneration; cell growth; clinically relevant; combinatorial; effective therapy; glial cell-line derived neurotrophic factor; improved; member; motor recovery; nerve supply; neural circuit; neuronal cell body; neuroprotection; neurotransmission; neurotrophic factor; novel; novel therapeutic intervention; overexpression; prevent; protective effect; receptive field; repaired; synaptogenesis; transmission process; treatment group; vector

Project Summary Spinal cord injury (SCI) is among the most disabling conditions affecting wounded members of the U.S. military. Unfortunately, no effective treatment has been available for patients with SCI. Developing novel repair strategies to mitigate the devastating nature of SCI and translating them to the clinic are urgent medical needs for our veterans with SCI. For functional recovery to occur after a SCI, regenerated axons need to follow the topography of grafted cells/growth factors and make accurate connections with specific subsets of neurons or subregions of dendritic architecture. The lumbar motoneurons (MNs) are the final common pathways for motor output to the hindlimbs and they undergo dendritic atrophy and synaptic stripping after an above-level SCI. The goal of our research is to reestablish neural circuitry across the lesion gap and to promote functional recovery after SCI. We hypothesize that a growth promoting pathway composed of grafted Schwann cells (SCs) overexpressing a growth factor called glial cell line-derived neurotrophic factor (GDNF) will promote the growth of descending propriospinal tract (dPST) axons across the lesion gap with extension caudally to the lumbar MNs in the host spinal cord, and that these axons will form target-specific synaptic contacts with lumbar MNs overexpressing a neurotrophin called neurotrophin-3 (NT-3). We also hypothesize that such a combinatorial approach will lead to greater recovery of function than either single treatment. Using a clinically-relevant contusive SCI model at the 9th thoracic (T9) level, transplantation of SCs-GDNF to form a continuous axonal growth-promoting pathway across and beyond a SCI, and adeno-associated virus serotype 2 expressing NT-3 (AAV2-NT-3) gene transfer approach to enhance NT-3 expression in lumbar MNs, we will determine (1) whether a continuous axonal growth-promoting pathway formed by grafted SCs-GDNF will promote dPST axonal growth through and beyond a contusive SCI, innervate the lumbar MNs pools, and enhance electrophysiological and locomotor recoveries; (2) whether combining the axonal growth-promoting pathway formed by SCs-GDNF with expression of NT-3 in lumbar MNs will synergistically enhance the innervation of dPST axons on lumbar MNs and, therefore, promote better recovery of function as compared to either treatment alone; (3) whether dPST-MN neurotransmission is necessary for hindlimb locomotor recovery in the combinatorial treatment; and (4) the molecular signature of lumbar MNs after the reestablishment of dPST-MN circuitry and synaptogenesis. Completion of this proposal will allow us to reveal mechanisms fundamental to rebuilding neural circuitry of the dPST-MN pathway and to identify new therapeutic strategies for locomotor recovery after clinically-relevant contusive SCIs.

项目摘要 脊髓损伤（SCI）是影响美国军方受伤成员的最残疾条件之一。 不幸的是，SCI患者尚无有效的治疗方法。开发新颖的维修 减轻SCI的毁灭性性质并将其转化为诊所的策略是紧迫的医疗需求 对于我们有科幻的退伍军人。为了在SCI后发生功能恢复，需要遵循再生的轴突 移植细胞/生长因子的地形，并与神经元的特定子集或 树突建筑的子区域。腰运动神经元（MN）是电动机的最终通用途径 输出后肢体，它们在高级SCI之后进行树突状萎缩和突触剥离。这 我们研究的目标是重建整个病变间隙的神经回路并促进功能恢复 科幻之后。我们假设促进由移植的Schwann细胞（SCS）组成的生长途径 过表达的生长因子称为神经胶质细胞系衍生的神经营养因子（GDNF）将促进生长 横跨病变间隙的降落前脊椎区（DPST）轴突的延伸至腰部 宿主脊髓中的MN，并且这些轴突将与腰部MN形成目标特异性突触接触 过表达一种称为Neurotrophin-3（NT-3）的神经营养蛋白。我们还假设这样的组合 与任何一种单一治疗相比，方法都会导致功能恢复更大。使用与临床相关的 在第9胸部（T9）水平上的Concoci模型，SCS-GDNF的移植以形成连续的轴突 跨SCI和超越SCI的生长途径，并与腺相关的病毒血清型2表达NT-3 （AAV2-NT-3）基因转移方法增强腰部MN中NT-3表达的方法，我们将确定（1） 嫁接的SCS-GDNF形成的连续轴突生长途径是否会促进DPST 轴突的生长通过和超越污染性的SCI，支配腰部MNS池并增强 电生理和运动恢复； （2）是否结合轴突生长途径 由SCS-GDNF与NT-3在腰部MN中的表达形成，将协同增强 腰部MN上的DPST轴突，因此，与任何一个 单独治疗； （3）DPST-MN神经传递是否需要用于后肢运动恢复 组合治疗； （4）DPST-MN重建后的腰肌的分子特征 电路和突触发生。该提案的完成将使我们能够揭示基本的机制 重建DPST-MN途径的神经回路，并确定运动的新治疗策略 与临床相关的污染性SCI后的恢复。