Mechanisms of age-related susceptibility of NMJ function

NMJ 功能与年龄相关的易感性机制

• 批准号: 9921270
• 负责人: Carlos B Mantilla
• 金额: $ 40.68万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921270
• 关键词: Adult; Affinity; Age; Autophagocytosis; Brain-Derived Neurotrophic Factor; Cell Death; Denervation; Development; Elderly; Foundations; Functional disorder; Genetic; Goals; Health; Impairment; Individual; Injury; Knock-in Mouse; Knowledge; Life; Longevity; Lysosomes; Maintenance; Measures; Mediating; Methods; Molecular; Motor; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle function; Nerve Degeneration; Neuromuscular Junction; Neurons; Performance; Phosphotransferases; Play; Predisposition; Property; Recycling; Role; Signal Transduction; Site; Solid; Stress; Structure; Testing; Tropomyosin; United States; age effect; age group; age related; aged; aging population; base; chemical genetics; combat; comorbidity; design; disability; experimental study; frailty; functional decline; gain of function; healthspan; innovation; loss of function; mortality; motor behavior; neuromuscular; neuromuscular system; neuromuscular transmission; neuronal survival; new therapeutic target; overexpression; protein aggregation; receptor; resilience; response; sarcopenia; sensor; targeted treatment

ABSTRACT The goal of this application is to determine the role of trophic interactions in the susceptibility (or resilience) to the effects of aging on the neuromuscular system. Age-related neuromuscular dysfunction is an important determinant of overall health, limiting independence, increasing frailty and predisposing individuals to age- related co-morbidities and mortality. Interactions between motoneurons and the muscle fibers they innervate determine muscle fiber properties and have a significant impact on muscle function throughout the lifespan. Motoneuron-muscle fiber interactions are likely exerted via trophic factors that vary across muscle groups. Brain-derived neurotrophic factor (BDNF) acting via its high-affinity receptor tropomyosin related kinase receptor (TrkB) has a known role in the maintenance of the adult NMJ. However, the role of BDNF/TrkB signaling in old age is not presently understood. Exciting recent studies show that inhibition of TrkB kinase activity exerts deleterious effects on neuromuscular transmission that vary across age groups, replicating the effects of old age at young NMJs. The current proposal will use a combination of highly-innovative methods to explore mechanistically the role of disrupted trophic factor signaling at the NMJ in old age. Our working hypothesis is that susceptibility to age-related neuromuscular dysfunction depends on motoneuron-muscle fiber trophic influences exerted by BDNF/TrkB signaling at the NMJ (aim 1) and motoneuron (aim 2). Furthermore, trophic factors can determine susceptibility to neuromuscular damage resulting from autophagy imbalance causing accumulation of protein aggregates and degeneration in old age. Two specific aims are proposed: Specific Aim 1) To determine the cellular (trophic factor dependent) mechanisms underlying susceptibility to neuromuscular dysfunction in old age. Specific Aim 2) To determine the molecular (trophic factor dependent) mechanisms underlying age-related effects at motoneurons. These results constitute the necessary foundation for the development of targeted therapies to mitigate aging effects on neuromuscular performance and increase the health span in the aging population with therapies initiated later in life to combat frailty and disability.

抽象的 该应用的目的是确定营养相互作用在易感性（或弹性）中的作用 衰老对神经肌肉系统的影响。与年龄有关的神经肌肉功能障碍是重要的 决定整体健康的决定因素，限制独立性，增加脆弱和诱人的个人为年龄 相关的合并症和死亡率。运动神经元与肌肉纤维之间的相互作用它们支配 确定肌肉纤维的特性，并在整个生命周期中对肌肉功能产生重大影响。 运动神经元肌肉纤维的相互作用可能是通过肌肉群中不同的营养因素施加的。 通过其高亲和力受体tropomyosin相关激酶作用的脑源性神经营养因子（BDNF） 受体（TRKB）在成年NMJ的维持中具有已知作用。但是，BDNF/TRKB的作用 目前尚不了解老年的信号。令人兴奋的最近研究表明，抑制TRKB激酶 活动对各个年龄段的神经肌肉传播产生有害影响，复制 年轻NMJS的老年人的影响。当前的建议将使用高度创新的方法组合 在机械上探索机械探索的营养因子信号在老年中的NMJ中的作用。我们的工作 假设是对年龄相关的神经肌肉功能障碍的敏感性取决于运动神经元肌肉 BDNF/TRKB信号在NMJ（AIM 1）和Motoneuron（AIM 2）施加的纤维营养影响。 此外，营养因素可以确定自噬引起的神经肌肉损害的敏感性 失衡导致蛋白质聚集体的积累和老年变性。两个具体目标是 提议：具体目的1）确定基础的细胞（营养因子依赖性）机制 老年人对神经肌肉功能障碍的敏感性。特定目标2）确定分子（营养 因子依赖性）机制在运动神经元中与年龄相关的作用。这些结果构成了 开发有针对性疗法以减轻对神经肌肉的衰老影响的必要基础 在以后开始的疗法以战斗的疗法中，性能并增加衰老人口的健康范围 脆弱和残疾。