THE ROLE OF AGRIN/LRP4/MUSK/DOK-7 SIGNALING IN DISASSEMBLY OF NEUROMUSCULAR SYNAPSES DURING AGING.

AGRIN/LRP4/MUSK/DOK-7 信号在衰老过程中神经肌肉突触分解中的作用。

• 批准号: 9145624
• 负责人: Steven Burden
• 金额: $ 42.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145624
• 关键词: Adult; Aging; Agonist; Agrin; Antibodies; Attenuated; Autoantibodies; Axon; Basal lamina; Binding; Birth; C-terminal; Cleaved cell; Complex; Deterioration; Epitopes; Genetic; Health; Human; Laminin; Maintenance; Motor; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle denervation procedure; Mutate; Myasthenia Gravis; N-terminal; Nerve; Play; Postsynaptic Membrane; Reporting; Respiratory Diaphragm; Role; Signal Transduction; Site; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; Testing; Therapeutic; Time; Tyrosine Phosphorylation; design; genome editing; in vivo; insight; nerve supply; neuromuscular; neuromuscular function; novel therapeutics; protein expression; research study; sarcopenia

 DESCRIPTION (provided by applicant): The formation and maintenance of neuromuscular synapses requires a mutual exchange of signals between motor neurons and muscle fibers, which is essential for the assembly and stability of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal, critical for fast, robust and reliable synaptic transmission. Agrin, Lrp4, MuSK and Dok-7 are required both to form and to maintain neuromuscular synapses. As such, a reduction in their expression or activity may be responsible for the simplification and loss of nerve terminals and disassembly of the postsynaptic membrane during aging. One attractive hypothesis suggests that proteolytic cleavage of Agrin, releasing the C-terminal Lrp4-binding region of Agrin from the synaptic cleft, contributes to synaptic disassembly during aging. We will directly test this idea in the first aim.In the second aim, we will determine whether the expression of other key signaling components, Lrp4, MuSK and Dok-7, as well as the level of MuSK tyrosine phosphorylation, decreases during aging. In the third aim, we will determine whether boosting synaptic signaling with an agonist antibody to MuSK, which stimulates MuSK tyrosine phosphorylation independent of Agrin and Lrp4, slows or halts the deterioration of neuromuscular synapses during aging. The experiments described here should provide new insights into the mechanisms that control synaptic disassembly during aging and have the potential to identify a novel therapeutic strategy for preserving the structure and function of neuromuscular synapses and reducing sarcopenia.

 描述(申请人提供)：神经肌肉突触的形成和维持需要运动神经元和肌肉纤维之间的相互信号交换，这对高度专门化的突触后膜和高度分化的神经末梢的组装和稳定至关重要，对于快速、稳健和可靠的突触传递至关重要。Agin、Lrp4、Musk和Dok-7是形成和维持神经肌肉突触所必需的。因此，它们的表达或活性的减少可能是导致神经末梢的简化和丢失以及突触后膜在衰老过程中解体的原因。一个有吸引力的假说认为，AGRIN的蛋白水解性裂解，将AGRIN的C端Lrp4结合区从突触裂隙中释放出来，有助于在衰老过程中突触的解体。我们将在第一个目标中直接测试这一想法。在第二个目标中，我们将确定其他关键信号组件Lrp4、Musk和Dok-7的表达以及Musk酪氨酸磷酸化水平是否随着年龄的增长而下降。在第三个目标中，我们将确定用麝香激动剂抗体增强突触信号，这种抗体刺激麝香酪氨酸磷酸化，而不依赖于AGRIN和Lrp4，是否减缓或阻止神经肌肉突触在衰老过程中的恶化。这里描述的实验应该为在衰老过程中控制突触分解的机制提供新的见解，并有可能确定一种新的治疗策略，以保存神经肌肉突触的结构和功能，并减少石棺减少。