Neuromuscular junction regeneration

神经肌肉接头再生

• 批准号: 10047696
• 负责人: Lin Mei
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047696
• 关键词: Affect; Agrin; Amyotrophic Lateral Sclerosis; Cholinergic Receptors; Denervation; Duchenne muscular dystrophy; Exercise; General Population; Glare; Goals; Impairment; Injury; LDL-Receptor Related Proteins; Laboratories; MUSK gene; Maintenance; Membrane; Molecular; Motor; Motor Neurons; Mus; Muscle; Muscle Contraction; Muscle Fibers; Muscular Atrophy; Mutation; Natural regeneration; Nerve; Neurodegenerative Disorders; Neuromuscular Junction; Peripheral; Peripheral nerve injury; Process; Progressive Bulbar Palsy; Protein Tyrosine Kinase; Recovery; Recovery of Function; Research; Role; Signal Transduction; Skeletal Muscle; Soldier; Synapses; Testing; Therapeutic Intervention; Time; Veterans; War; Work; agrin receptor; base; combat wound; improved; limb injury; nerve injury; nervous system disorder; postsynaptic; reinnervation; repaired

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.

我们研究的长期目标是了解潜在的功能恢复机制 肌肉和神经损伤。在本提案中，我们将重点关注神经肌肉的再生。 交界处(NMJ)。NMJ是一种将运动神经元的信号传递给肌肉纤维的突触 来控制肌肉收缩。骨骼肌和周围神经损伤在 士兵参加与战斗无关的活动，如锻炼。他们的发病率显著增加。 在战争时期。事实上，四肢受伤是战伤的主要原因。 在骨骼肌和周围神经损伤中，NMJ不可避免地受到损害。在……里面 此外，肌肉会因各种周围神经退行性疾病而失神经，如 肌萎缩侧索硬化症、Duchenne-Aran肌萎缩和进行性球麻痹， 其中许多对退伍军人的影响比普通民众更大。从肌肉/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 特别是NMJ的再生，通过这个过程，失神经肌肉通过以下方式重新神经 运动神经。然而，与神经和肌肉修复/再生不同的是，人们对此知之甚少 损伤肌肉再神经支配的分子机制，这是我们的研究中的一个明显空白 了解肌肉/神经损伤后的功能恢复。因此，具有治疗作用 促进NMJ再生的干预措施有限。最近的研究揭示了关键的 NMJ组装和维护机制。有证据表明，agrin信号是 不仅对NMJ的形成很重要，而且对它的维持也是必要的。这些进展 为研究NMJ再生机制提供了有利条件。在本提案中，我们将测试 假设集聚蛋白信号对损伤后NMJ的再生至关重要，并且 Agrin信号促进NMJ再生。研究结果将使我们更好地了解 NMJ再生中的集聚蛋白信号，开发更好的治疗干预的先决条件 肌肉/神经损伤的战斗创伤和周围神经疾病发生在 退伍军人中的发病率更高。