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Mechanisms of age-related susceptibility of NMJ function

NMJ 功能与年龄相关的易感性机制

基本信息

批准号：
10161705
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161705
关键词：
Adult Affinity 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 human old age (65+)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

项目摘要

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.

摘要