Neuromuscular junction regeneration

我们研究的长期目标是了解功能恢复的潜在机制， 肌肉和神经损伤在这个建议中，我们将集中在神经肌肉的再生 结（NMJ）。NMJ是一种突触，将信号从运动神经元传递到肌肉纤维 来控制肌肉收缩骨骼肌和周围神经损伤是常见的 士兵在非战斗相关的活动，如演习。他们的发病率显著增加 在战争时期。事实上，肢体受伤占战斗创伤的大多数。 不可避免地，NMJ在骨骼肌和外周神经损伤中受损。在 此外，肌肉在各种周围神经退行性疾病中变得失神经支配， 肌萎缩性侧索硬化症、杜兴-阿然肌萎缩症和进行性延髓麻痹， 其中许多对退伍军人的影响比普通民众更大。肌肉/神经恢复 损伤和周围神经退行性疾病需要神经再生、肌肉修复和修复， 特别是NMJ再生，这是一个过程，通过这个过程，去神经支配的肌肉变得再神经支配， 运动神经然而，与神经和肌肉修复/再生不同， 损伤肌肉的神经再支配的分子机制，这是我们的一个明显的差距， 了解肌肉/神经损伤的功能恢复。因此，治疗 促进NMJ再生的干预措施有限。最近的研究表明， NMJ组装和维护的机制。有证据表明，聚集蛋白信号传导是 不仅对NMJ的形成很重要，而且对NMJ的维持也很必要。这些进步 为研究NMJ再生机制提供了一个利基。在本提案中，我们将测试 聚集蛋白信号传导对损伤后NMJ再生至关重要， 聚集蛋白信号传导促进NMJ再生。结果将提供更好的理解 NMJ再生中的聚集蛋白信号传导，开发更好的治疗干预的先决条件 用于治疗因战斗创伤造成的肌肉/神经损伤和发生在 退伍军人的比例更高。

The long term goal of our study is to understand mechanisms underlying functional recovery from muscle and nerve injuries. In this proposal we will focus on regeneration of the neuromuscular junction (NMJ). The NMJ is a synapse that transmits signals from motor neurons to muscle fibers to control muscle contraction. Skeletal muscle and peripheral nerve injuries are common among soldiers in non-battle related activities such as exercise. Their incident rate increases significantly during war time. In fact, extremity injuries account for the majority of combat wounds. Unavoidably, the NMJ becomes damaged in skeletal muscle and peripheral nerve injuries. In addition, muscles become denervated in various peripheral neurodegenerative disorders like amyotrophic lateral sclerosis, Duchenne-Aran muscular atrophy and progressive bulbar palsy, many of which affect veterans more than the general population. Recovery from muscle/nerve injuries and peripheral neurodegenerative disorders requires nerve regrowth, muscle repair and in particular NMJ regeneration, a process by which denervated muscles become reinnervated by motor nerves. However, unlike nerve and muscle repair/regeneration, much less is known about molecular mechanisms of reinnervation of injury muscles, which is a glaring gap in our understanding of functional recovery from muscle/nerve injury. Consequently, therapeutic interventions to promote NMJ regeneration are limited. Recent studies have revealed critical mechanisms for NMJ assembly and maintenance. Evidence indicates that the agrin signaling is not only important for NMJ formation, but also necessary for its maintenance. These advances provide a niche to study mechanisms of NMJ regeneration. In this proposal, we will test the hypotheses that agrin signaling is critical for NMJ regeneration after injury and that increasing agrin signaling promotes NMJ regeneration. The results will provide a better understanding of agrin signaling in NMJ regeneration, a prerequisite to developing better therapeutic intervention for muscle/nerve injury from combat wounds and peripheral neurological disorders that occur at higher rates among veterans.