Spinal cord injury, paralysis and neuromuscular junctions

脊髓损伤、瘫痪和神经肌肉接头

• 批准号: 8251685
• 负责人: YOUNG-JIN SON
• 金额: $ 13.4万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251685
• 关键词: Spinal; cord; injury; paralysis; neuromuscular

DESCRIPTION (provided by applicant): Several different therapeutic approaches have produced significant recovery of motor function in experimental models of spinal cord injury (SCI). These treatments include strategies designed to enhance axon regeneration and strategies targeted towards remyelination, tissue sparing and training the spared circuits. Their potential usefulness at the bedside, however, is critically dependent on nerve-muscle connectivity that not only remains functional but also functions as efficiently as possible. Surprisingly, however, the synaptic responses of muscles to SCI have received little attention, and the neuromuscular junctions (NMJs) caudal to SCI are assumed to remain intact. Our preliminary morphological analyses, however, suggest that NMJs in hindlimb muscles of adult rats paralyzed by SCI may be extremely dysfunctional. Furthermore, these studies imply that adult NMJs may be extraordinarily diverse and specific in their sensitivity to paralysis. In this R21 application, we will use fluorescent transgenic mice, in vivo time-lapse imaging, and combined electrophysiological and morphological analyses to determine (1) if there are multiple subpopulations of NMJs that differ in pre- and postsynaptic sensitivity to the SCI-elicited paralysis, and (2) if physiologically significant loss of nerve-muscle connectivity accompanies morphological instability of NMJs distal to SCI. These results will provide critical data to justify a larger grant application to: explore the molecular mechanisms underlying the unexpected diversity of mature NMJs; comprehensively assess the contribution of NMJ loss to motor deficits associated with SCI; and attempt to promote motor recovery by stabilizing NMJs. The proposed work therefore has the potential to establish a strong foundation for developing novel treatments for spinal cord injured patients. PUBLIC HEALTH RELEVANCE: Several different therapeutic approaches have produced significant recovery of motor function in experimental models of spinal cord injury. These treatments include strategies designed to enhance axon regeneration and strategies targeted towards remyelination, tissue sparing and training the spared circuits. The project seeks to provide a novel basis for motor deficits and recovery following spinal cord injury by identifying nerve-muscle connections, termed neuromuscular junctions, as novel therapeutic targets.

描述（由申请人提供）：几种不同的治疗方法已经在脊髓损伤（SCI）的实验模型中产生了运动功能的显着恢复。这些治疗包括旨在增强轴突再生的策略和针对髓鞘再生、组织保留和训练保留回路的策略。然而，它们在床边的潜在用途很大程度上取决于神经肌肉的连接，这种连接不仅保持功能，而且尽可能有效地发挥作用。然而，令人惊讶的是，肌肉对 SCI 的突触反应很少受到关注，并且 SCI 尾部的神经肌肉接头 (NMJ) 被认为保持完整。然而，我们的初步形态学分析表明，因 SCI 导致瘫痪的成年大鼠后肢肌肉中的 NMJ 可能极度功能障碍。此外，这些研究表明，成人 NMJ 对麻痹的敏感性可能极其多样化和特异性。在此 R21 应用中，我们将使用荧光转基因小鼠、体内延时成像以及组合的电生理学和形态学分析来确定 (1) 是否存在对 SCI 引发的突触前和突触后敏感性不同的多个 NMJ 亚群瘫痪；(2) SCI 远端 NMJ 的形态不稳定是否伴有神经肌肉连接的生理学显着丧失。这些结果将提供关键数据来证明更大规模的资助申请的合理性：探索成熟 NMJ 意外多样性背后的分子机制；全面评估 NMJ 损失对 SCI 相关运动缺陷的影响；并尝试通过稳定 NMJ 来促进运动恢复。因此，拟议的工作有可能为开发脊髓损伤患者的新疗法奠定坚实的基础。公众健康相关性：几种不同的治疗方法已使脊髓损伤实验模型的运动功能显着恢复。这些治疗包括旨在增强轴突再生的策略和针对髓鞘再生、组织保留和训练保留回路的策略。该项目旨在通过确定神经肌肉连接（称为神经肌肉接头）作为新的治疗靶点，为脊髓损伤后的运动缺陷和恢复提供新的基础。

项目成果

ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions.

ProBDNF 和成熟 BDNF 作为小鼠神经肌肉接头处突触消除的惩罚和奖励信号。

• 发表时间: 2013-06-12
• 作者: Je, H Shawn;Yang, Feng;Ji, Yuanyuan;Potluri, Srilatha;Fu, Xiu;Luo, Zhen;Nagappan, Guhan;Chan, Jia Pei;Hempstead, Barbara;Son, Young;Lu, Bai
• 通讯作者: Lu, Bai

Phosphate glass fibres promote neurite outgrowth and early regeneration in a peripheral nerve injury model.

磷酸盐玻璃纤维促进周围神经损伤模型中的神经突生长和早期再生。

• 发表时间: 2015-03
• 作者: Kim, Young;Lee, Gil;Kim, Jong;Kim, Min Soo;Ahn, Hong;Lim, Jae;Kim, Hae;Son, Young;Knowles, Jonathan C;Hyun, Jung Keun
• 通讯作者: Hyun, Jung Keun

Serial changes in bladder, locomotion, and levels of neurotrophic factors in rats with spinal cord contusion.

脊髓挫伤大鼠膀胱、运动和神经营养因子水平的连续变化。

• 发表时间: 2009-10
• 影响因子: 4.2
• 作者: Hyun, Jung Keun;Lee, Young Il;Son, Young;Park, Jeong
• 通讯作者: Park, Jeong

Inhibition of Kinesin-5, a microtubule-based motor protein, as a strategy for enhancing regeneration of adult axons.

抑制 Kinesin-5（一种基于微管的运动蛋白）作为增强成年轴突再生的策略。

• 发表时间: 2011-03
• 作者: Lin, Shen;Liu, Mei;Son, Young;Timothy Himes, Barry;Snow, Diane M;Yu, Wenqian;Baas, Peter W
• 通讯作者: Baas, Peter W

In vivo imaging of dorsal root regeneration: rapid immobilization and presynaptic differentiation at the CNS/PNS border.

背根再生的体内成像：CNS/PNS 边界的快速固定和突触前分化。

• 发表时间: 2011-03-23
• 作者: Di Maio, Alessandro;Skuba, Andrew;Himes, B Timothy;Bhagat, Srishiti L;Hyun, Jung Keun;Tessler, Alan;Bishop, Derron;Son, Young
• 通讯作者: Son, Young