The Primate Corticospinal Connectome and Transcriptome

灵长类动物皮质脊髓连接组和转录组

• 批准号: 10650134
• 负责人: MARK H. TUSZYNSKI
• 金额: $ 63.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650134
• 关键词: Adult; Affinity Chromatography; Axon; Brain; Cells; Cervical spinal cord structure; Corticospinal Tracts; Data; Distal; Embryo; Genes; Genetic Transcription; Grant; Growth; Hand; Human; Injury; Interneurons; Intervention; Knowledge; Label; Lesion; Macaca mulatta; Monkeys; Motor; Motor Cortex; Motor Neurons; Mus; Natural regeneration; Nature; Neurons; Pathway interactions; Primates; Property; Rattus; Recovery Support; Recovery of Function; Reporting; RiboTag; Ribosomes; Rodent; Series; Site; Spinal Cord; Spinal cord injury; Synapses; System; Therapeutic Intervention; Time; Translations; Up-Regulation; Viral; Viral Vector; Work; axon injury; axon regeneration; cell type; connectome; critical period; functional improvement; improved; injured; motor control; nerve stem cell; neural; neural graft; novel; programs; regenerative; severe injury; stem cells; time use; transcriptome; transcriptome sequencing

Project Summary Efforts to promote recovery of function after human spinal cord injury (SCI) will likely require interventions targeting the corticospinal motor system, the most important pathway for voluntary motor control in humans. In a series of studies over the past 4 years we have found that corticospinal tract (CST) axons regenerate into spinal cord neural stem cell (NSC) grafts placed into sites of SCI in mice, rats and monkeys. These regenerating CST axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord. Neural relays across the injury are thereby formed, supporting functional improvement. This work is on a human translational path and IND-enabling work is in progress. This grant proposes two new directions that will be critically important in supporting human translation. First, we recently reported that injured adult mouse CST neurons revert to an embryonic transcriptional state that lasts for two weeks after SCI, a time during which CST axons can regenerate. This finding establishes a critical period for intervention after mouse SCI to support recovery. Does the same transcriptional reversion to a pro-growth embryonic state occur in the primate brain? If so, how long does it last? Work in Aim 1 will definitively answer this question, identifying for the first time what may be an optimal time window for therapeutic intervention of any type to support functional recovery in primates, including humans. We will perform RNA sequencing (RNAseq) specifically of CST neurons after SCI in rhesus monkeys using intersectional viral approaches, based on supportive preliminary data in monkeys. In Aim 2 we propose for the first time using novel viral vectors to anterogradely, trans-synaptically trace primate corticospinal projections to the spinal cord. Our preliminary studies demonstrate that rodent CST axons project nearly entirely to spinal cord interneurons, whereas in primates the vast preponderance of CST axons terminate directly on alpha motor neurons. Knowing the precise targets of CST projections to the spinal cord will both markedly extend our basic knowledge of motor system organization in primates, and will allow optimization of stem cell graft properties to enhance neural relay formation across sites of SCI. Unlike other neural stem cell programs for SCI, our work aims to directly re-form critical neural relays across a severe injury, rather than target spared axons through grafts of OPCs; knowledge gained from this aim could markedly improve relay formation across injury sites in the primate system.

项目摘要 促进人脊髓损伤（SCI）后恢复功能的努力可能需要干预 针对皮质脊髓运动系统，这是自愿电机控制的最重要途径 人类。在过去四年中的一系列研究中，我们发现皮质脊髓（CST）轴突 再生为脊髓神经干细胞（NSC）移植物，放入小鼠，大鼠和大鼠的SCI部位 猴子。这些再生的CST轴突与移植物形成突触，移植物又延伸非常延伸 从损伤部位长距离进入脊髓的大量新轴突。神经 因此形成了整个伤害的继电器，支持功能改善。这项工作是在人类上 翻译路径和索引工作正在进行中。 该赠款提出了两个新的方向，这些方向对于支持人类翻译至关重要。 首先，我们最近报告说，受伤的成年小鼠CST神经元恢复为胚胎转录 指出SCI后持续两个星期，在此期间CST轴突可以再生。这个发现 建立小鼠SCI后干预的关键时期以支持恢复。也一样 在灵长类动物的大脑中，转录回归为增生的胚胎状态吗？如果是这样，多长时间 它持续了吗？ AIM 1的工作将确定回答这个问题，首次确定可能是什么 任何类型的治疗干预的最佳时间窗口，以支持灵长类动物的功能恢复， 包括人类。我们将在SCI中专门执行CST神经元的RNA测序（RNASEQ） 基于猴子的支持性初步数据，使用交叉病毒方法的恒河猴。 在AIM 2中，我们首次提出使用新型病毒矢量进行前射线，突触的痕迹 灵长类动物皮质脊髓投射到脊髓。我们的初步研究表明啮齿动物CST 轴突几乎完全针对脊髓中间神经元，而在灵长类动物中 CST轴突直接终止于α运动神经元上。知道CST预测的确切目标 脊髓将显着扩展我们对灵长类动物的运动系统组织的基本知识， 并将允许优化干细胞移植的特性，以增强跨的位置的神经继电器形成 科学。与其他有关SCI的神经干细胞程序不同，我们的工作旨在直接重新形成关键神经 跨严重损伤的继电器，而不是通过OPC的移植物靶向保存的轴突；知识获得了 从这个目标中可以显着改善灵长类动物系统中跨伤害部位的接力。