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（Spinal cord injury，SCI）是一种严重的疾病，其死亡率高， 发病率不幸的是，SCI患者还没有有效的治疗方法。腰椎 运动神经元（MN）是运动输出到后肢的最终共同通路。任何损害这些 MN可导致后肢瘫痪和肌肉萎缩。当SCI发生在腰部以上时，即 在水平以上的损伤中，腰椎MN不会直接受到创伤的损害，但它们会经历深刻的损伤。 树突萎缩和突触剥离。虽然迄今为止大多数SCI研究都集中在再生或 保护受伤的脊髓在损伤部位，很少有研究探讨如何调制腰椎MN 在一个以上级别的SCI后，电路会影响病理和功能后果。我们的目标是 开发一种针对高位SCI后腰椎MN的有益恢复治疗， 解剖出个体传入通路如何影响腰椎MN重塑和功能恢复。在这 应用，我们提出了一个中心假设，即增加腰椎MN池的局部NT-3水平将刺激 从不同的传入通路募集备用轴突，并增强它们的突触形成， 腰椎MN。因此，在腰椎水平重建神经回路形成了 脊髓损伤后后肢功能恢复。因此，提出了三个具体目标， 研究影响腰椎MN功能的三种主要传入途径，以确定它们在NT中的作用， 3-介导的腰椎运动回路重塑和胸部SCI后的后肢恢复。这些途径 包括下行网状脊髓束（RetST）、下行固有脊髓束（dPST）和 背根（DR）传入。一旦每个特定通路的功能作用被定义，我们将使用 针对多个途径的组合方法以最大化治疗效果。这将由 唱 成年小鼠胸9（T9）挫伤性SCI模型和AAV 2-NT-3基因转移方法以增加 MN中NT-3水平。

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