Characterization of Chronic Contusive Spinal Cord Injury and Promotion of Corticospinal Tract Regeneration

慢性挫伤性脊髓损伤的特征及促进皮质脊髓束再生

• 批准号: 10292951
• 负责人: Pengzhe Lu
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292951
• 关键词: Acute; Adult; Affect; Afghanistan; American; Americas; Animal Model; Animals; Apoptosis; Atrophic; Axon; Back; Bilateral; Bioinformatics; Candidate Disease Gene; Caring; Cervical; Cervical spinal cord structure; Chronic; Cicatrix; Contusions; Corticospinal Tracts; Data; Data Set; Development; Disease; Down-Regulation; Exhibits; Expeditions; Extracellular Matrix; Feeling; Fishes; Functional disorder; Future; Generations; Genes; Genetic Transcription; Grant; Growth; Hand functions; Histologic; Human; In Vitro; Injury; Knowledge; Lesion; Lesion by Stage; Messenger RNA; Methods; Microglia; Mission; Modeling; Molecular; Motor; Movement; Natural regeneration; Neurites; Neuroglia; Neurons; Outcome; Paralysed; Pathway interactions; Patient Care; Process; Quadriplegia; Quality of life; Rattus; Recovery; Refractory; Research; RiboTag; Signal Transduction; Spinal Cord; Spinal Cord Contusions; Spinal Ganglia; Spinal cord injury; Spinal cord injury patients; Stem cell transplant; System; Techniques; Testing; Time; Tissues; Veterans; War; Work; axon growth; axon injury; axon regeneration; base; clinically relevant; experience; guided inquiry; in vivo evaluation; injured; loss of function; molecular pathology; molecular targeted therapies; motor axon regeneration; motor control; nerve stem cell; neurite growth; neuronal cell body; novel therapeutics; postnatal; success; therapeutic development; therapy development; tool; transcriptome; transcriptome sequencing; vector

Characterization of Chronic Contusive Spinal Cord Injury and Promotion of Corticospinal Tract Regeneration Summary Chronic spinal cord injury (SCI) is a post-injury stage when the injury is stable with little additional change. Although the vast majority of SCI are chronic, there are few studies to characterize the chronic injury at histological, cellular, and molecular level in clinical relevant animal models. There are even fewer studies for development of therapeutic treatment of chronic SCI, especially for promotion of supraspinal motor axonal regeneration, including the corticospinal tract (CST) system that is the most important voluntary motor control system in humans. Therefore, we propose to use a chronic clinical relevant moderate bilateral lower cervical contusion model for characterization it at cellular and molecular levels and development of new therapies for improvement of skilled hand function. There are three Specific Aims in this proposal. Aim 1 is to identify cellular mechanisms associated with chronic contusive SCI, to guide discovery of new molecular mechanisms to promote regeneration. We will develop a moderate chronic bilateral lower (C6) cervical contusion model since the majority of SCI patients (65%) are quadriplegic, with loss of hand function that is critical for independence and quality of life. The injured rats survive for up to 12 months to a chronic stage of SCI for characterization of glial scar, extra cellular molecules (ECM) and axonal state. Aim 2 is to identify transcriptional mechanisms associated with chronic contusive SCI, to guide discovery of new molecular mechanisms to promote regeneration. We will use a newly developed technique developed in our lab, Cre-dependent Ribotag vectors, to isolate mRNA specific from chronically injured CST neurons for characterization of their transcriptome using RNAseq. We then compare this transcriptome to intact and sub-acutely injured CST neurons (we already have these datasets) and chronically injured CST neurons that regenerate into neural progenitor cell (NPC) graft to identify key molecular pathways related to cellular/axonal growth that are disrupted, We can therapeutically target these molecular pathways in Aim 3 and future studies. Aim 3 is to test candidate mechanisms to promote recovery of chronically injured CST neurons and promote axonal regeneration after chronic SCI. We will first perform in vitro screen for the potential candidate targets identified in Aim2 to promote neurite growth of postnatal cortical neurons and adult dorsal root ganglion (DRG) neurons. We then test these candidate genes to promote regeneration of chronically injured CST in combination with NPC transplants that serve as a permissive cellular substrate. Findings of this work will substantially extend our knowledge of chronic SCI and develop potential treatment for chronic SCI.

慢性挫伤性脊髓损伤的特征及促进 皮质脊髓束再生 概括 慢性脊髓损伤 (SCI) 是损伤后的一个阶段，此时损伤稳定，几乎不需要额外的治疗 改变。尽管绝大多数 SCI 是慢性的，但很少有研究来描述慢性 SCI 的特征。 临床相关动物模型中组织学、细胞和分子水平的损伤。甚至还有 开发慢性 SCI 治疗方法的研究较少，尤其是促进 脊髓上运动轴突再生，包括最重要的皮质脊髓束（CST）系统 人类重要的自主运动控制系统。因此，我们建议使用慢性临床 相关的中度双侧下颈椎挫伤模型，用于在细胞和分子方面表征它 提高手部熟练功能的水平和新疗法的开发。 该提案有三个具体目标。目标 1 是确定相关的细胞机制 与慢性挫伤性脊髓损伤，指导新分子机制的发现，以促进 再生。我们将开发中度慢性双侧下颈椎（C6）挫伤模型 大多数 SCI 患者 (65%) 是四肢瘫痪，手部功能丧失对于脊髓损伤至关重要 独立性和生活质量。受伤的大鼠存活长达 12 个月，直至进入 SCI 慢性阶段 用于表征神经胶质疤痕、细胞外分子 (ECM) 和轴突状态。目标 2 是确定 与慢性挫伤性 SCI 相关的转录机制，以指导新发现 促进再生的分子机制。我们将使用新开发的技术 我们的实验室开发了 Cre 依赖性 Ribotag 载体，用于从慢性损伤中分离特异性 mRNA 使用 RNAseq 表征 CST 神经元的转录组。然后我们比较这个 完整和亚急性损伤的 CST 神经元的转录组（我们已经有了这些数据集）和 慢性损伤的 CST 神经元可再生为神经祖细胞 (NPC) 移植物，以识别关键的 与细胞/轴突生长相关的分子途径被破坏，我们可以以治疗为目标 目标 3 和未来研究中的这些分子途径。目标 3 是测试候选机制 促进慢性损伤的 CST 神经元的恢复并促进轴突再生 慢性脊髓损伤。我们将首先对 Aim2 中确定的潜在候选靶标进行体外筛选，以 促进出生后皮质神经元和成年背根神经节 (DRG) 神经元的神经突生长。我们 然后测试这些候选基因以促进慢性损伤的 CST 的再生 NPC 移植物作为允许的细胞基质。这项工作的结果将在很大程度上 扩展我们对慢性 SCI 的了解并开发慢性 SCI 的潜在治疗方法。

项目成果

Rehabilitation combined with neural progenitor cell grafts enables functional recovery in chronic spinal cord injury.

康复与神经祖细胞移植相结合可以使慢性脊髓损伤的功能恢复。

• 发表时间: 2022-08-22
• 影响因子: 8
• 作者: Lu, Paul;Freria, Camila M;Graham, Lori;Tran, Amanda N;Villarta, Ashley;Yassin, Dena;Huie, J Russell;Ferguson, Adam R;Tuszynski, Mark H
• 通讯作者: Tuszynski, Mark H

Neural Stem Cells: Promoting Axonal Regeneration and Spinal Cord Connectivity.

神经干细胞：促进轴突再生和脊髓连接。

• 发表时间: 2021-11-25
• 影响因子: 6
• 作者: de Freria, Camila Marques;Van Niekerk, Erna;Blesch, Armin;Lu, Paul
• 通讯作者: Lu, Paul