Functional aging of neuromuscular junctions in C. elegans

 描述(申请人提供)：随着人类年龄的增长，我们在许多方面都会经历不可避免的生理变化，包括运动活动。事实上，与年龄相关的运动活动进行性下降是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缺陷被认为是年龄相关性运动功能下降的原因。尽管进行了广泛的研究，但NMJ在正常衰老过程中发生功能衰退的机制尚不清楚。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，这也仍然是一个挑战。线虫因其短的寿命和对遗传操作的适应性而成为研究衰老的一个很好的模型系统。在衰老过程中，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，同样的问题也出现了，即在老化的蠕虫中观察到的运动活动进行性下降的背后可能存在什么机制。最近，我们首次对线虫整个生命周期中老化的运动神经元和肌肉进行了功能分析。我们的结果表明，突触小泡融合的进行性下降，随后是运动神经元的量子大小和小泡停靠/启动，显着地导致了NMJ的年龄相关性功能下降。因此，在这项提案中，我们旨在进一步解决以下悬而未决的问题(目标1)：在生命早期观察到的运动神经元突触小泡融合功能下降的机制是什么？肌肉对观察到的运动神经元功能衰退有贡献吗？我们研究的一个长期目标是最终开发新的治疗策略，以防止或延缓老年人经常出现的与年龄相关的活动能力下降和疲劳性增加。因此，在这项建议的第二部分，我们将重点研究应用专门针对运动神经元突触传递给老年蠕虫的遗传学(目标2)和药理学(目标3)干预是否可以改善NMJ功能衰退并最终延长寿命。

 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.