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（由适用提供）：神经肌肉突触的形成和维护需要在运动神经元和肌肉纤维之间相互交流信号，这对于高度专业的突触后膜的组装和稳定性和高度分化的神经终端是至关重要的，对于快速，可靠的，可靠的，可靠的突触传输。需要Agrin，LRP4，Musk和Dok-7既需要形成并保持神经肌肉突触。因此，其表达或活性的降低可能是导致神经末端的简化和损失，并在衰老过程中拆卸突触后膜。一个有吸引力的假设表明，阿格林的蛋白水解裂解，从合成裂口中释放出Agrin的C末端LRP4结合区域，在衰老期间有助于突触拆卸。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成分LRP4，Musk和Dok-7的表达以及在衰老过程中降低的Musk酪氨酸磷酸化水平是否会降低。在第三个目标中，我们将确定使用对麝香的激动剂抗体来促进合成信号传导，该抗体是否刺激了独立于Agrin和LRP4的Musk酪氨酸磷酸化，在衰老过程中会减慢或停止神经肌肉突触的恶化。此处描述的实验应提供对控制衰老过程中控制突触拆卸的机制的新见解，并有潜力确定一种新型的治疗策略，以保留神经肌肉突触的结构和功能并减少肌肉减少症。