Functional aging of neuromuscular junctions in C. elegans

 描述（由申请人提供）：随着人类年龄的增长，我们在许多领域都经历了不可避免的生理变化，包括运动活动。事实上，运动活动的年龄依赖性进行性下降代表了衰老动物和人类最显著的生理变化之一。神经肌肉接头（NMJ）是连接运动神经元和肌肉的功能单位。NMJ的缺陷被认为是运动功能年龄依赖性下降的基础。尽管进行了广泛的研究，NMJ在正常衰老过程中发生功能下降的机制还没有得到很好的理解。它也仍然是一个挑战，是否以及如何干预NMJ的功能下降可以改善老年人的运动功能，并最终延长寿命。线虫C.秀丽隐杆线虫由于其寿命短和易于遗传操作，最近成为衰老研究的良好模型系统。在老化过程中，C.秀丽线虫还表现出许多与高等生物相似的衰老表型，包括与年龄相关的运动活动下降。然而，同样的问题出现了，什么机制可能是在老化蠕虫中观察到的运动活动逐渐下降的基础。最近，我们首次对C.优雅我们的研究结果表明，在突触囊泡融合的进行性下降，其次是在量子大小和囊泡对接/启动的运动神经元显着有助于与年龄相关的功能下降的NMJ。因此，在这个提议中，我们的目标是进一步解决以下未回答的问题（目标1）：在早期生活中观察到的运动神经元突触囊泡融合功能下降的机制是什么？肌肉是否会导致运动神经元功能下降？我们研究的一个长期目标是最终开发新的治疗策略，可以预防或延迟老年人经常发生的与年龄相关的活动能力下降和疲劳增加。因此，在本提案的第二部分，我们将重点研究是否应用遗传（目标2）和药理学（目标3）干预，专门针对运动神经元突触传递老年蠕虫可以改善NMJ功能下降，并最终延长寿命。

 DESCRIPTION (provided by applicant): As humans age, we experience inevitable physiological changes in many areas, including motor activity. In fact, age-dependent progressive decline in motor activity represents one of the most prominent physiological changes in aging animals and humans. Neuromuscular junctions (NMJs) are the functional units that connect motor neurons and muscles. Deficits at NMJs are believed to underlie age-dependent decline in motor function. Despite extensive studies, the mechanisms by which NMJs undergo functional decline during normal aging are not well understood. It also remains a challenge as to whether and how intervening functional decline at NMJs can improve motor function in the elderly and ultimately extend lifespan. The nematode C. elegans has recently emerged as a good model system for aging studies because of its short lifespan and amenability to genetic manipulation. During aging, C. elegans also exhibits many aging phenotypes that resemble those found in higher organisms, including the age-related decline in motor activity. However, the same question arises as to what mechanisms may underlie the progressive decline in motor activity observed in aging worms. Recently, we have performed the first functional analysis of the aging motor neurons and muscles throughout the lifespan of C. elegans. Our results suggested that the progressive decline in the synaptic vesicle fusion followed by that in quantal size and vesicle docking/priming of motor neurons significantly contribute to the age-related functional decline of NMJs. Therefore, in this proposal, we aim to further address the following unanswered questions (Aim 1): What are the mechanisms underlying the observed functional decline in synaptic vesicle fusion in motor neurons in early life? Do muscles contribute to the observed functional decline in motor neurons? A long-term goal of our research is to ultimately develop new therapeutic strategies that could prevent or delay the age-related declines in mobility and increases in fatigability that often occur in the elderly population. Thus, in the second part of this proposal, we will focus on investigating whether applying genetic (Aim 2) and pharmacological (Aim 3) interventions specifically targeting the motor neuron synaptic transmission to aged worms can ameliorate NMJ functional decline and ultimately extend lifespan.