Age, Injury, and the Neuromuscular Junction

年龄、损伤和神经肌肉接头

• 批准号: 10738374
• 负责人: Sarah M Greising
• 金额: $ 15.17万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738374
• 关键词: Activities of Daily Living; Address; Age; Aging; Applications Grants; Area; Biogenesis; Biology of Aging; Breathing; Cells; Chronic; Clinical; Codependence; Collaborations; Contracts; Data; Denervation; Development; Doctor of Philosophy; Education; Effectiveness of Interventions; Elderly; Environment; Evaluation; Failure; Fiber; Fostering; Foundations; Functional disorder; Genomics; Goals; Health; Impairment; Independent Scientist Award; Injury; International; Intervention; K-Series Research Career Programs; Kinesiology; Knowledge; Link; Longevity; Metabolic; Metabolic dysfunction; Minnesota; Mitochondria; Modality; Motor; Motor Neurons; Movement; Muscle; Muscle Contraction; Muscle Fibers; Neuromuscular Junction; Operative Surgical Procedures; Outcome; Pathologic; Pathology; Pathway interactions; Physiology; Population; Public Health; Publishing; Recovery; Regenerative capacity; Rehabilitation therapy; Research; Schools; Scientist; Signal Transduction; Site; Skeletal Muscle; Skeletal muscle injury; Synapses; Techniques; Time; Traumatic injury; United States; Universities; Work; age related; aged; aging population; career; comorbidity; design; disability; exercise training; frailty; functional decline; functional disability; functional improvement; functional restoration; healthspan; human old age (65+); improved; mid-career faculty; mitochondrial dysfunction; mortality; negative affect; nerve supply; neuromuscular; neuromuscular function; neuromuscular system; neuromuscular transmission; novel; overexpression; recruit; regeneration function; regeneration potential; repaired; response; sarcopenia; skeletal muscle wasting; tool; volumetric muscle loss

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).

摘要 独立科学家奖（K 02）的申请旨在促进重要的知识， 了解NMJ年龄相关变化的机制，并支持Sarah M博士的职业生涯。变油腻， 明尼苏达大学运动机能学院副教授。老年人 美国的人口继续增加，有一个持续的科学必要性，以了解 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）的基本评价，运动神经元和 骨骼肌纤维NMJ启动肌肉收缩，并允许身体运动，包括能力 在生命周期中呼吸。没有神经支配，肌肉纤维就不能收缩，从而显著降低功能。 该K 02应用程序的总体目标是表征和纠正神经肌肉缺陷和低 可塑性在骨骼肌老化和损伤后，通过评估是否共享的机制， NMJ的不稳定性存在。这项建议将利用两种病理， 骨骼肌的潜力，通过评估NMJ在中老年和以下的老化轨迹 肌肉体积损失（VML），临床上确定为骨骼肌的慢性和不可恢复的损失 导致功能障碍的组织。衰老和VML损伤都导致相当多的神经肌肉损伤， 功能障碍和慢性合并症。我的中心假设是，老年人进行性NMJ不稳定 受伤的骨骼肌在肌肉中创造了一个不利的细胞环境， 干预措施的有效性。我提出了两个具体的目标来解决这些假设：1）理解 减少神经支配和NMJ不稳定的限制;和2）为了确定在 在渐进式不稳定中的NMJ。拟议研究的结果将确定细胞机制 这有助于受伤和衰老后剩余肌肉的有限适应和再生能力， 这与NMJ的不稳定有何关系K 02奖的既定目标是促进以下方面的发展： 杰出的科学家，使他们能够扩大他们的潜力，使他们的领域作出重大贡献， research.这个K 02奖将推动和重振Greising博士在衰老生物学方面的科学发展 通过提供有保护的时间：1）为有竞争力的NIA建立初步数据和概念框架 R 01级拨款提案，2）评估老年和受损骨骼肌中NMJ失调的机制， 和3）建立我的教育和理解omics为基础的工具，以发展合作，能够问， 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 （专业知识）。