Agrin signaling in maintaining neuromuscular junction in aging

 描述（由申请人提供）：在衰老过程中，骨骼肌萎缩并失去收缩力。这影响到大量的老年人，不分种族、性别， 这是与年龄相关的独立性丧失、虚弱和死亡的最常见原因。随着人口中老年人比例的不断增加，肌肉老化的潜在社会和经济负担变得巨大。神经肌肉接头是运动神经元末梢和骨骼肌纤维之间的突触，其将信号从运动神经元传递到肌肉纤维。神经肌肉传递对于控制肌肉收缩至关重要，因此对于我们的身体活动和日常生活至关重要。广泛的研究揭示了肌肉衰老的病理生理机制。然而，尽管NMJ结构和功能在老年动物中被破坏，但对其潜在机制知之甚少。与已经被广泛研究的NMJ形成相反，对NMJ维持机制的了解少得多，特别是在老年动物中。该提案将测试一个创新的假设，即老年动物的NMJ功能取决于聚集蛋白信号传导，这是NMJ形成所需的途径。特别是，我们将通过使用尖端技术的组合来解决以下关键问题。首先，LRP 4缺乏模仿LRP 4减少老年小鼠引起NMJ下降？恢复聚集蛋白信号传导是否改善老年小鼠的NMJ功能？控制LRP 4稳定性的机制是什么？聚集蛋白信号是如何维持老年小鼠NMJ功能的？结果将提供明确的证据，支持或反驳，聚集蛋白信号参与NMJ下降在老化过程中，揭示增强聚集蛋白信号是否可以防止或延迟NMJ下降和肌肉老化，并确定新的机制控制LRP 4的稳定性和介导聚集蛋白信号，以促进NMJ的维护。这些知识可能有助于更好地理解NMJ下降和肌肉老化的分子机制，这是开发NMJ下降和肌肉老化的有效治疗干预措施的先决条件。

 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.