Functional aging of neuromuscular junctions in C. elegans

线虫神经肌肉接头的功能老化

• 批准号: 9282385
• 负责人: Ao-Lin Allen Hsu
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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/9282385
• 关键词: Address; Affect; Age; Aging; Aging-Related Process; Animal Model; Animals; Area; Arecoline; Behavior; Biological Models; Caenorhabditis elegans; Calcium Channel; Deterioration; Docking; Elderly; Employee Strikes; Exhibits; Exocytosis; Frail Elderly; Genetic; Goals; Human; Intervention; Lead; Life; Locomotion; Longevity; Mammals; Membrane; Michigan; Molecular; Motor; Motor Activity; Motor Neurons; Muscle; Nematoda; Neuromuscular Junction; Organism; Pathway interactions; Pharmacology; Phenotype; Physiological; Physiology; Population; Research; Role; Study models; Synapses; Synaptic Transmission; Synaptic Vesicles; Testing; Universities; Vesicle; age related; aged; experience; functional decline; functional status; gene therapy; genetic manipulation; insight; interdisciplinary approach; large-conductance calcium-activated potassium channels; motor function improvement; muscle form; muscle strength; neurophysiology; normal aging; novel; novel therapeutic intervention; patch clamp; paxilline; prevent; public health relevance; quantum; skeletal muscle wasting; synaptic function; therapeutic development; therapy development; tool; voltage

 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.

 描述（由适用提供）：随着人类的年龄，我们在包括运动活动在内的许多领域经历了不可避免的身体变化。实际上，运动活动依赖年龄的渐进式下降是衰老动物和人类最突出的生理变化之一。神经肌肉连接（NMJS）是连接运动神经元和肌肉的功能单元。据信，NMJ的缺陷是运动功能依赖年龄的下降的基础。尽管进行了广泛的研究，但在正常衰老期间NMJ经历功能下降的机制尚不清楚。对于NMJS的中断功能下降是否可以改善过去并最终延长寿命的运动功能，这也仍然是一个挑战。线虫秀丽隐杆线虫最近成为一个良好的模型系统，用于衰老研究，因为它的寿命短，并且对遗传操作的适合性。在衰老期间，秀丽隐杆线虫还表现出许多类似于在较高生物体中发现的衰老表型，包括与年龄相关的运动活动下降。但是，出现了同样的问题，即哪种机制可能是衰老蠕虫中观察到的运动活动逐渐下降的基础。最近，我们对秀丽隐杆线虫的整个生命周期进行了对衰老运动神经元和肌肉的首次功能分析。我们的结果表明，突触囊泡融合的逐渐下降，其次是数量大小和运动神经元的囊泡对接/启动，这显着有助于NMJ与年龄相关的功能下降。因此，在此提案中，我们的目标是进一步解决以下未解决的问题（AIM 1）：早期运动神经元中观察到的突触囊泡融合功能下降的机制是什么？肌肉会导致运动神经元观察到的功能下降吗？我们研究的一个长期目标是最终制定新的治疗策略，这些策略可以预防或延迟与年龄相关的流动性下降和疲劳性的增加，而疲劳性通常会发生在老年人群中。在本提案的第二部分中，我们将重点研究应用遗传（AIM 2）和药物（AIM 3）干预措施，该干预措施专门针对运动神经元突触传播到老年蠕虫是否可以改善NMJ功能下降并最终延长寿命。