Age, Injury, and the Neuromuscular Junction

摘要 本独立科学家奖(K02)的申请旨在促进对以下领域具有重要意义的知识 了解NMJ年龄相关变化的机制，并支持Sarah M.Greing博士的职业生涯， 他是明尼苏达大学运动学学院的副教授。作为老年人 美国的人口在持续增加，有必要从科学上理解 老年神经肌肉功能障碍的原因。了解神经肌肉功能障碍需要 神经肌肉接头(NMJ)是运动神经元和神经细胞之间的接触点 骨骼肌纤维。NMJ启动肌肉收缩，并允许身体运动，包括能力 在整个生命周期中呼吸。如果没有神经支配，肌肉纤维就不能收缩，从而显著降低功能。 此K02应用程序的总体目标是表征和纠正神经肌肉缺陷和低血压 通过评估衰老和损伤后骨骼肌可塑性的共同机制 NMJ的不稳定是存在的。这项提议将利用两种再生能力有限的病理。 通过评估中老年和以下年龄段的NMJ来评估骨骼肌的潜力 容积性肌肉丢失(VML)，临床上被认为是一种慢性的、不可恢复的骨骼肌丢失 导致功能损伤的组织。衰老和VML损伤都会导致相当大的神经肌肉 功能障碍和慢性并存。我的中心假设是老年人进行性的NMJ不稳定 受损的骨骼肌在肌肉中创造了一个敌对的细胞环境，从而减轻了可塑性和钝化。 干预措施的有效性。我提出了两个具体目标来解决这些假设：1)理解 神经支配减弱和NMJ失稳的限度；以及2)确定在什么地方发生空间变化 NMJ在逐渐不稳定期间。拟议的研究结果将确定细胞机制。 这有助于损伤和衰老后剩余肌肉有限的适应和再生能力 这与NMJ的不稳定有何关系。K02奖项的既定目标是促进 杰出的科学家，并使他们能够扩大他们的潜力，为他们的领域做出重大贡献 研究。这项K02奖将推动和重振格里辛博士在衰老生物学方面的科学发展 通过为以下方面提供受保护的时间：1)为具有竞争力的NIA构建初步数据和概念框架 R01级拨款建议，2)评估老年和损伤骨骼肌NMJ失调的机制， 以及3)培养我对基于组学的工具的教育和理解，以开发能够询问和 回答有影响力的问题，将NMJ的生理学(我的专业知识)和这些新技术联系起来 (协作专业知识)。

Abstract This application for an Independent Scientist Award (K02) is designed to advance knowledge important for understanding mechanisms of age-related changes at the NMJ and support the career of Dr. Sarah M. Greising, PhD, an Associate Professor in the School of Kinesiology at the University of Minnesota. As the elderly population of the United States continues to increase there is an ongoing scientific necessity to understand the causes of neuromuscular dysfunction in old age. Understanding neuromuscular dysfunction requires fundamental evaluations of the neuromuscular junction (NMJ) the point of contact between a motor neuron and skeletal muscle fiber. The NMJ initiates muscle contraction and allows physical movement including the ability to breathe across the lifespan. Without innervation, muscle fibers cannot contract, significantly reducing function. The overall objective of this K02 application is to characterize and correct neuromuscular deficiency and low plasticity in the skeletal muscle following both aging and injury by evaluating if shared mechanisms of destabilization of the NMJ exist. This proposal will capitalize on two pathologies that have limited regenerative potential of skeletal muscle by evaluating the NMJ across the aging trajectory of mid- to old-age and following volumetric muscle loss (VML), which is clinically identified as a chronic and irrecoverable loss of skeletal muscle tissue resulting in functional impairments. Both aging and VML injury result in considerable neuromuscular dysfunction, and chronic co-morbidities. My central hypothesis is that progressive NMJ destabilization in aged and injured skeletal muscle create a hostile cellular environment in the muscle that mitigates plasticity and blunts the effectiveness of interventions. I propose two specific aims to address these hypotheses: 1) To understand the limits of diminished innervation and NMJ destabilization; and 2) To determine what spatial changes occur at the NMJ during progressive destabilization. The results of the proposed studies will define cellular mechanisms that contribute to the finite adaptive and regenerative capacity of the remaining muscle after injury and aging and how this relates to NMJ destabilization. The stated goal of the K02 award is to foster the development of outstanding scientists and enable them to expand their potential to make significant contributions to their field of research. This K02 award will advance and reinvigorate Dr. Greising’s scientific development in aging biology by providing protected time to: 1) to build preliminary data and a conceptual framework for a competitive NIA R01-level grant proposal, 2) evaluate mechanisms of NMJ dysregulation in aged and injured skeletal muscle, and 3) build my education and understanding of omics-based tools to develop collaborations able to ask and answer impactful questions linking the physiology of the NMJ (my expertise) and these novel techniques (collaborative expertise).