Agrin signaling in maintaining neuromuscular junction in aging

集聚蛋白信号传导在衰老过程中维持神经肌肉接头

基本信息

批准号：
9145617
负责人：
Lin Mei
金额：
$ 38万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
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/9145617
关键词：
Address Affect Age Aging Agrin Animals Atrophic Attenuated Caloric Restriction Cells Collagen Type VI Complex Development Dystrophin Economic Burden Elderly Ethnic Origin Extracellular Matrix Proteins Functional disorder Gender Glycoproteins Health Knowledge Life Maintenance Mediating Messenger RNA Molecular Motor Neurons Mus Muscle Muscle Contraction Muscle Fibers Muscular Dystrophies Mutant Strains Mice Mutation Neuromuscular Junction Pathway interactions Phosphorylation Play Population Protein Tyrosine Kinase Research Role Sarcoglycans Sequence Analysis Signal Transduction Skeletal Muscle Structure Surface Synapses Technology Testing Therapeutic Intervention Two-Hybrid System Techniques age related aged agrin receptor density frailty improved in vivo innovation insight knock-down mortality muscle aging muscle strength mutant neuromuscular transmission novel overexpression prevent social transcriptome sequencing yeast protein

项目摘要

DESCRIPTION (provided by applicant): During aging, skeletal muscles become atrophic and lose contractile force. This affects a large population of elderly regardless of ethnicity, gender, and wealth and is the most common cause of age-related loss of independence, frailty, and mortality. As the elderly proportion in the population continues to increase, the potential social and economic burden of muscle aging is becoming enormous. The neuromuscular junction is a synapse between motor neuron terminals and skeletal muscle fibers that transmit signals from motor neurons to muscle fibers. The neuromuscular transmission is critical for the control of muscle contraction and is thus essential for our physical mobility and daily life. Extensive research has revealed insight into the pathophysiological mechanisms of muscle aging. However, although NMJ structures and functions are disrupted in aged animals, little is known about underlying mechanisms. In contrast to NMJ formation, which has been studied extensively, much less is understood about mechanisms of NMJ maintenance, in particular in aged animals. This proposal will test an innovative hypothesis that NMJ function in aged animals depends on agrin signaling, a pathway that is required for NMJ formation. In particular, we will address the following critical questions by using a combination of cutting edge technologies. First, does LRP4 deficiency mimicking LRP4 reduction in aged mice cause NMJ decline? Does restoring agrin signaling improve NMJ function in aged mice? What is the mechanism that controls LRP4 stability? How does agrin signaling maintain NMJ function in aged mice? Results will provide unequivocal evidence to either support or refute that agrin signaling is involved in NMJ decline during aging, reveal whether enhancing agrin signaling may prevent or delay NMJ decline and muscle aging, and identify novel mechanisms controlling LRP4 stability and mediating agrin signaling to promote NMJ maintenance. Such knowledge may contribute to a better understanding of molecular mechanisms of NMJ decline and muscle aging, which is prerequisite to the development of effective therapeutic interventions for NMJ decline and muscle aging.

描述（由申请人提供）：在衰老过程中，骨骼肌会萎缩并失去收缩力，这会影响大量老年人，无论其种族、性别、性别如何。神经肌肉接头是与年龄相关的独立性丧失、虚弱和死亡的最常见原因。运动神经元末梢和骨骼肌纤维之间的突触，将信号从运动神经元传递到肌肉纤维，神经肌肉传输对于肌肉收缩的控制至关重要，因此对于我们的身体活动和日常生活至关重要。然而，尽管老年动物的 NMJ 结构和功能受到破坏，但与已研究的 NMJ 形成相反，人们对 NMJ 维持机制的了解却少之又少。该提案将测试一个创新假设，即老年动物中的 NMJ 功能取决于 agrin 信号传导，这是 NMJ 形成所需的途径。特别是，我们将通过结合使用尖端技术来解决以下关键问题。第一的， LRP4 缺乏会导致老年小鼠的 NMJ 下降吗？恢复 agrin 信号传导是否会改善老年小鼠的 NMJ 功能？控制 LRP4 稳定性的机制是什么？结果将为我们提供明确的证据。支持或反驳 agrin 信号传导参与衰老过程中的 NMJ 衰退，揭示增强 agrin 信号传导是否可以预防或延缓 NMJ 衰退和肌肉衰老，并确定控制的新机制LRP4 稳定性和介导 agrin 信号传导以促进 NMJ 维持，这些知识可能有助于更好地了解 NMJ 衰退和肌肉衰老的分子机制，这是开发针对 NMJ 衰退和肌肉衰老的有效治疗干预措施的先决条件。