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(申请人提供)：在脊髓损伤(SCI)的实验模型中，几种不同的治疗方法已经产生了显著的运动功能恢复。这些治疗包括旨在促进轴突再生的策略，以及针对重新髓鞘形成、组织保护和训练备用回路的策略。然而，它们在床边的潜在用处关键取决于神经-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，肌肉对脊髓损伤的突触反应几乎没有受到关注，对脊髓损伤的神经肌肉接头(NMJ)尾部被认为保持完好。然而，我们的初步形态分析表明，脊髓损伤瘫痪的成年大鼠后肢肌肉中的NMJ可能功能极度失调。此外，这些研究表明，成年NMJ对麻痹的敏感度可能非常不同和特殊。在这个R21的应用中，我们将使用荧光转基因小鼠，活体时间推移成像，并结合电生理和形态学分析来确定(1)是否有多个NMJ亚群对脊髓损伤诱发的瘫痪具有不同的突触前和突触后敏感性，以及(2)是否生理上显著的神经肌肉连接丧失伴随着脊髓损伤远端NMJ的形态不稳定性。这些结果将为更大规模的拨款申请提供关键数据：探索成熟NMJ意外多样性背后的分子机制；全面评估NMJ丢失对与脊髓损伤相关的运动障碍的贡献；并试图通过稳定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治疗方法奠定坚实的基础。公共卫生相关性：在脊髓损伤的实验模型中，几种不同的治疗方法已经产生了显着的运动功能恢复。这些治疗包括旨在促进轴突再生的策略，以及针对重新髓鞘形成、组织保护和训练备用回路的策略。该项目旨在通过确定神经-肌肉连接，称为神经肌肉连接，作为新的治疗靶点，为脊髓损伤后的运动障碍和恢复提供新的基础。

项目成果

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

• DOI: 10.1111/j.1600-0854.2010.01152.x
• 发表时间: 2011-03
• 期刊: Traffic (Copenhagen, Denmark)
• 作者: Lin S;Liu M;Son YJ;Timothy Himes B;Snow DM;Yu W;Baas PW
• 通讯作者: Baas PW

Live imaging of dorsal root regeneration and the resurgence of a forgotten idea.

• DOI: 10.1227/01.neu.0000400019.16401.c3
• 发表时间: 2011-08
• 期刊: Neurosurgery
• 影响因子: 4.8
• 作者: Amgad S. Hanna;Y. Son;R. Dempsey

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

• DOI: 10.1523/jneurosci.4638-10.2011
• 发表时间: 2011-03-23
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Di Maio A;Skuba A;Himes BT;Bhagat SL;Hyun JK;Tessler A;Bishop D;Son YJ
• 通讯作者: Son YJ

Live imaging of dorsal root axons after rhizotomy.

根切断术后背根轴突的实时成像。

• DOI: 10.3791/3126
• 发表时间: 2011
• 期刊: Journal of visualized experiments : JoVE
• 作者: Skuba,Andrew;Himes,BTimothy;Son,Young-Jin
• 通讯作者: Son,Young-Jin

Time-lapse in vivo imaging of dorsal root nerve regeneration in mice.

小鼠背根神经再生的延时体内成像。

• DOI: 10.1007/978-1-4939-0777-9_18
• 发表时间: 2014
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Skuba,Andrew;Manire,MeredithAnn;Kim,Hyukmin;Han,SeungBaek;Son,Young-Jin
• 通讯作者: Son,Young-Jin