Neuromuscular Activity: Development and Survival of Avian and Mammalian Neurons

神经肌肉活动：鸟类和哺乳动物神经元的发育和生存

• 批准号: 7341121
• 负责人: RONALD W OPPENHEIM
• 金额: $ 34.23万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341121
• 关键词: Adult; Affect; Amyotrophic Lateral Sclerosis; Apoptotic; Axon; Biological Assay; Birds; Brain Diseases; Cell Adhesion Molecules; Cell Communication; Cell Death; Cells; Cessation of life; Chromosome Pairing; Chronic; Development; Embryo; Goals; Intracellular Second Messenger; Intramuscular; Mediating; Molecular; Motor Neurons; Mus; Muscle; Neonatal; Nerve; Neurodegenerative Disorders; Neurons; Numbers; Onset of illness; Pathway interactions; Primary Lateral Sclerosis; Production; Proteins; Regulation; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Spinal; Spinal Muscular Atrophy; Synapses; Testing; design; extracellular; in vitro Model; in vivo; in vivo Model; mRNA Expression; neuromuscular activity; neuronal survival; neurotrophic factor; novel; novel strategies; prenatal; research study; retrograde transport; second messenger; uptake

The major goal of this application is to examine the cellular and molecular mechanisms that mediate activity-dependent motoneuron survival during development in avian (chick) and mammalian (mouse) embryos. Chronic activity blockade during the period of naturally occurring motoneuron death promotes motoneuron survival. Previous studies are supportive of the hypothesis that neuromuscular activity in the embryo modulates intramuscular axon branching which in turn provides access of motoneurons to muscle- derived neurotrophic factors via uptake and retrograde transport of these factors by axonal branches/terminals. An alternataive explanation is that activity regulates the production (synthesis or release) of target muscle-derived neurotrophic factors (e.g., loss of activity increases production resulting in the rescue of motoneurons). A third novel hypothesis proposes that activity blockade rescues motoneruons by a neurotrophic factor independent pathway. Three specific aims are proposed to examine each of these alternative (but not necessarily mutually exclusive) explanations of activity-dependent MN survival. In the first aim, neurotrophic factor expression (mRNA, protein) will be assayed in muscles and nerves following in vivo perturbations of activity. In the secondaim, the role of cell adhesion molecule-mediated changes in intramuscular axon branching following perburbations of activity will be examined. In the third aim, intracellular second messenger signaling pathways will be examined in an attempt to determine whether distinct molecular mechanisms are involved in motoneuron survival mediated by neurotorphic factros ys following perturbations of activity. Collectively, the proposed studies provide novel approaches for elucidating the mechanisms involved in activity-dependent motoneuron survival in vivo, that will advance our understanding of developmental neuronal death. They also have the potential to expand our conceptualization of pathological motoneuron death by revealing ways in which alterations in neuromuscular activity may be a contributing factor in neurodegenerative diseases such as amyuotrophic lateral sclerosis (ALS) and spinal muscular atropohy (SMA).

该应用的主要目的是检查介导的细胞和分子机制 活性依赖性的运动神经元在发育过程中的生存期（小鸡）和哺乳动物（小鼠） 胚胎。自然发生的运动神经元死亡期间的慢性活动阻滞促进 Motoneuron生存。先前的研究支持了一种假设，即神经肌肉活性 胚胎调节肌内轴突分支，这又提供了运动神经元进入肌肉的访问 通过轴突摄取和逆行转运来衍生的神经营养因子 分支/终端。另一种解释是，活动调节生产（合成或 释放目标肌肉衍生的神经营养因素（例如，活动丧失会增加产量，导致产生 营救运动神经元）。第三个新颖的假设提出活动阻滞拯救莫诺鲁恩 通过神经营养因子独立途径。提出了三个具体目标来检查每个目标 这些替代性（但不一定是相互排斥的）解释依赖活性的MN存活。在 第一个目的是在肌肉和神经中测定神经营养因子的表达（mRNA，蛋白质） 遵循活动的体内扰动。在Seconsaim中，细胞粘附分子介导的作用 将检查肌肉内轴突分支的变化。在第三 目的，将检查细胞内的第二信通过信号通路，以确定 神经局介导的运动神经元存活中是否涉及不同的分子机制 在活动的扰动之后。 拟议的研究共同提供了阐明涉及机制的新方法 与活动有关的运动神经元生存在体内，这将提高我们对发展的理解 神经元死亡。他们也有可能扩大我们对病理运动神经元的概念 通过揭示神经肌肉活性改变的方法可能是导致因素 神经退行性疾病，例如肌营养性侧面硬化症（ALS）和脊髓肌肉肌动蛋白 （SMA）。