Spinal cord injury, paralysis and neuromuscular junctions

脊髓损伤、瘫痪和神经肌肉接头

• 批准号: 7531518
• 负责人: YOUNG-JIN SON
• 金额: $ 19.69万
• 依托单位: DREXEL UNIVERSITY
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531518
• 关键词: Acetylcholine; Adult; Appendix; Applications Grants; Attention; Axon; Brain; Burn injury; Cholinergic Receptors; Chromosome Pairing; Class; Data; Denervation; Development; Disruption; Distal; Elements; Experimental Models; Figs - dietary; Foundations; Functional disorder; Hindlimb; Image; Individual; Lead; Life; Maintenance; Measures; Molecular; Monitor; Motor; Motor Neurons; Mus; Muscle; Muscle Fibers; Natural regeneration; Nerve; Neuromuscular Junction; Neurotoxins; Operative Surgical Procedures; Paralysed; Patients; Physiological; Population; Public Health; Rattus; Recovery; Reporting; Resistance; Safety; Signal Transduction; Spinal Cord; Spinal cord injury; Staging; Synapses; Synaptic Transmission; Testing; Therapeutic; Thinking; Thoracic spinal cord structure; Time; Tissues; Training; Transgenic Mice; Vulnerable Populations; Work; axon regeneration; base; design; in vivo; innovation; insight; motor deficit; novel; novel therapeutics; postsynaptic; presynaptic; receptor; research study; response; size; therapeutic target; time use

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在脊髓损伤（SCI）的实验模型中产生了显著的运动功能恢复。这些治疗包括旨在增强轴突再生的策略和针对髓鞘再生、组织保留和训练备用电路的策略。然而，它们在床边的潜在用途严重依赖于神经-肌肉连接，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很少受到关注，脊髓损伤的神经肌肉连接（NMJs）被认为是完整的。然而，我们的初步形态学分析表明，脊髓损伤后成年大鼠后肢肌肉的NMJs可能是极度功能失调的。此外，这些研究表明，成年nmj对瘫痪的敏感性可能非常多样化和特异性。在这项R21应用中，我们将使用荧光转基因小鼠，体内延时成像，结合电生理和形态学分析来确定(1)是否存在多个NMJs亚群，它们在突触前和突触后对SCI诱发的麻痹的敏感性不同，以及(2)神经-肌肉连接的生理显著丧失是否伴随着SCI远端NMJs的形态学不稳定。这些结果将为更大的资助申请提供关键数据：探索成熟NMJs意想不到的多样性背后的分子机制；综合评估NMJ损失对脊髓损伤相关运动缺陷的贡献；并尝试通过稳定NMJs来促进运动恢复。因此，提出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：几种不同的治疗方法在脊髓损伤实验模型中产生了显著的运动功能恢复。这些治疗包括旨在增强轴突再生的策略和针对髓鞘再生、组织保留和训练备用电路的策略。该项目旨在通过识别神经肌肉连接（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缺陷和恢复提供新的基础。