Modulation of lumbar motor circuitry after an above-level SCI and NT-3 gene therapy

以上水平 SCI 和 NT-3 基因治疗后腰椎运动回路的调节

• 批准号: 10239210
• 负责人: George M Smith
• 金额: $ 37.84万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239210
• 关键词: Address; Adult; Affect; Afferent Pathways; Anatomy; Atrophic; Attenuated; Axon; Brain Stem; Cervical; Chest; Clinical; Contusions; Data; Electrophysiology (science); Gene Transfer; Goals; H-Reflex; Hindlimb; Human; Impairment; Individual; Injury; Locomotor Recovery; Measures; Mediating; Medical; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Motor Pathways; Motor output; Mus; Muscle; Muscular Atrophy; Natural regeneration; Neurons; Paralysed; Pathologic; Pathway interactions; Patients; Play; Pontine structure; Prevention; Recovery; Recovery of Function; Reticular Formation; Role; Sensory; Site; Spinal Cord Contusions; Spinal Ganglia; Spinal cord injury; Spinal cord injury patients; Synapses; Testing; Thoracic spinal cord structure; Translating; Trauma; United States; effective therapy; experience; functional disability; gene therapy; mortality; motor impairment; nerve supply; neural circuit; neurotransmission; novel; recruit; repair strategy; response; restorative treatment; reticulospinal tract; retrograde transport; sciatic nerve; spinal nerve posterior root; treatment effect

Spinal cord injury (SCI) is a severe medical problem experienced by humans with high mortality and long term morbidity. Unfortunately, there has been no effective treatment available for SCI patients. The lumbar motoneurons (MNs) are the final common pathway for motor output to the hindlimbs. Any impairment of these MNs can cause hindlimb paralysis and muscle atrophy. When SCI occurs above the lumbar level, namely above-level injury, the lumbar MNs are not directly damaged by the trauma, but they undergo profound dendritic atrophy and synaptic stripping. While most SCI studies to date have focused on the regeneration or protection of the injured spinal cord at the injury site, few studies have explored how modulation of lumbar MN circuitry would affect pathological and functional consequences after an above-level SCI. Our goal is to develop a beneficial restorative treatment targeting lumbar MNs after an above-level SCI and to functionally dissect out how individual afferent pathways affect lumbar MN remodeling and functional recovery. In this application, we propose a central hypothesis that increasing local NT-3 levels at lumbar MN pools will stimulate the recruitment of spared axons from distinct afferent pathways and enhance their synaptic formation onto lumbar MNs. Thus, reestablishment of neural circuitry at the lumbar level forms the anatomical basis for hindlimb functional recovery after an above-level SCI. Accordingly, three specific aims are proposed to investigate the three major afferent pathways to influencing lumbar MNs function to determine their roles in NT- 3-mediated remodeling of lumbar motor circuitry and hindlimb recovery after a thoracic SCI. These pathways include the descending reticulospinal tracts (RetST), the descending propriospinal tracts (dPST), and the dorsal roots (DR) afferents. Once the functional role of each specific pathway is defined, we will used combinational approaches to target multiple pathways to maximize the treatment effect. This will be done u sing an adult mouse thoracic 9 (T9) contusive SCI model and an AAV2-NT-3 gene transfer approach to increase the level of NT-3 in MNs.

脊髓损伤（SCI）是高死亡率和长期死亡人体遇到的严重医疗问题 发病率。不幸的是，SCI患者没有有效的治疗方法。腰 运动神经元（MNS）是给后肢发动机输出的最终通用途径。这些损害 MNS会导致后肢瘫痪和肌肉萎缩。当Sci发生在腰部水平以上时，即 高于级别的伤害，腰部MN并未受到创伤的直接损害，但他们经历了深刻的 树突状萎缩和突触剥离。迄今为止大多数SCI研究都集中在再生或 在受伤部位保护受伤的脊髓，很少有研究探讨了腰椎的调节 电路将影响高于SCI后的病理和功能后果。我们的目标是 在高级SCI之后，开发针对腰MN的有益的恢复性治疗，并在功能上 剖析单个传入途径如何影响腰椎MN重塑和功能恢复。在这个 应用，我们提出了一个中心假设，即腰椎MN池的局部NT-3水平增加将刺激 从不同的传入途径中募集了较不幸的轴突，并将其突触形成增强到 腰部MNS。因此，在腰椎层重建神经回路构成了解剖学基础 高级SCI之后的后肢功能恢复。因此，提出了三个具体目标 研究影响腰部MN功能的三个主要传入途径，以确定它们在NT-的作用 胸科SCI后3介导的腰运动电路和后肢恢复的重塑。这些途径 包括降落的网状脊髓（RETST），降脊髓脊髓（DPST）和 背根（DR）传入。一旦定义了每个特定途径的功能作用，我们将使用 结合靶向多种途径以最大化治疗效果的方法。这将完成你 唱歌 成年小鼠胸9（T9）coci Sci模型和AAV2-NT-3基因转移方法，以增加 MNS中的NT-3级。

项目成果

Retrogradely Transportable Lentivirus Tracers for Mapping Spinal Cord Locomotor Circuits.

用于绘制脊髓运动回路的逆行可运输慢病毒示踪剂。

• DOI: 10.3389/fncir.2018.00060
• 发表时间: 2018
• 期刊: Frontiers in neural circuits
• 影响因子: 3.5
• 作者: Sheikh,ImranS;Keefe,KathleenM;Sterling,NoelleA;Junker,IanP;Eneanya,ChidubemI;Liu,Yingpeng;Tang,Xiao-Qing;Smith,GeorgeM
• 通讯作者: Smith,GeorgeM