Neuromuscular junction regeneration

神经肌肉接头再生

• 批准号: 10647628
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647628
• 关键词: Affect; Agrin; Amyotrophic Lateral Sclerosis; Cholinergic Receptors; Denervation; Duchenne muscular dystrophy; Exercise; General Population; Goals; Growth; Heterozygote; 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; combat wound; improved; limb injury; nerve injury; nervous system disorder; postsynaptic; reinnervation; repaired; transmission process

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功能恢复的机制 肌肉和神经损伤。在此提案中，我们将重点放在神经肌肉的再生上 交界处（NMJ）。 NMJ是一个突触，将信号从运动神经元传输到肌肉纤维 控制肌肉收缩。骨骼肌和周围神经损伤很常见 非战斗与锻炼等非战斗活动的士兵。他们的事件率显着增加 战争期间。实际上，肢体伤害是大多数战斗伤口。 不可避免地，NMJ在骨骼肌和周围神经损伤中受损。在 此外，肌肉在各种外周神经退行性疾病中被取消 肌萎缩性侧面硬化症，Duchenne-Aran肌肉萎缩和进行性鳞茎麻痹， 其中许多对退伍军人的影响大于一般人口。从肌肉/神经中恢复 受伤和周围神经退行性疾病需要神经再生，肌肉修复和 特定的NMJ再生，这一过程被取消的肌肉被造成 运动神经。但是，与神经和肌肉修复/再生不同，对 损伤肌肉加剧的分子机制，这是我们的明显差距 了解肌肉/神经损伤的功能恢复。因此，治疗性 促进NMJ再生的干预措施有限。最近的研究揭示了关键 NMJ组装和维护的机制。证据表明Agrin信号是 不仅对NMJ组的形成很重要，而且对维护也是必要的。这些进步 为研究NMJ再生的机制提供利基。在此提案中，我们将测试 假设Agrin信号对于受伤后的NMJ再生至关重要 Agrin信号传导促进NMJ再生。结果将提供更好的理解 NMJ再生中的Agrin信号传导，这是开发更好治疗干预的先决条件 对于作战伤口和周围神经系统疾病而发生的肌肉/神经损伤 退伍军人的比率更高。

项目成果

Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation.

• DOI: 10.1016/j.neuron.2021.12.032
• 发表时间: 2022-01-19
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Xing G;Jing H;Yu Z;Chen P;Wang H;Xiong WC;Mei L
• 通讯作者: Mei L

Lrp4 in astrocytes modulates glutamatergic transmission.

星形胶质细胞中的 Lrp4 调节谷氨酸能传递

• DOI: 10.1038/nn.4326
• 发表时间: 2016-08
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Sun XD;Li L;Liu F;Huang ZH;Bean JC;Jiao HF;Barik A;Kim SM;Wu H;Shen C;Tian Y;Lin TW;Bates R;Sathyamurthy A;Chen YJ;Yin DM;Xiong L;Lin HP;Hu JX;Li BM;Gao TM;Xiong WC;Mei L
• 通讯作者: Mei L

Erbin is required for myelination in regenerated axons after injury.

损伤后再生轴突的髓鞘形成需要 Erbin

• DOI: 10.1523/jneurosci.2466-12.2012
• 发表时间: 2012-10-24
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Liang C;Tao Y;Shen C;Tan Z;Xiong WC;Mei L
• 通讯作者: Mei L