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: 7013359
• 负责人: RONALD W OPPENHEIM
• 金额: $ 36.24万
• 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/7013359
• 关键词: axon; biological signal transduction; cell adhesion molecules; cell death; chick embryo; confocal scanning microscopy; developmental neurobiology; gene expression; hepatocyte growth factor; immunologic assay /test; laboratory mouse; light emission; motor neurons; muscle contraction; neural cell adhesion molecules; neurogenesis; neuromuscular stimulator; neuromuscular system; neuronal guidance; neuronal transport; neurotrophic factors; polymerase chain reaction; psychomotor function; second messengers; tissue /cell culture; vertebrate embryology; axon; biological signal transduction; cell adhesion molecules; cell death; chick embryo; confocal scanning microscopy; developmental neurobiology; gene expression; hepatocyte growth factor; immunologic assay /test; laboratory mouse; light emission; motor neurons; muscle contraction; neural cell adhesion molecules; neurogenesis; neuromuscular stimulator; neuromuscular system; neuronal guidance; neuronal transport; neurotrophic factors; polymerase chain reaction; psychomotor function; second messengers; tissue /cell culture; vertebrate embryology

DESCRIPTION (provided by applicant): 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 alternative 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 motoneurons 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 second aim, the role of cell adhesion molecule-mediated changes in intramuscular axon branching following perturbations 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 neurotrophic factors 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 amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).

描述（由申请人提供）：本申请的主要目标是检查辅助活性依赖性运动神经元在发育过程中的细胞和分子机制。在天然发生的运动神经元死亡期间，慢性活动阻滞可促进运动神经元的存活。先前的研究支持了以下假设：胚胎中的神经肌肉活性调节肌内轴突分支，这又通过轴突/末端通过摄取和这些因子逆转来访问运动神经元来访问肌肉衍生的神经营养因子。另一种解释是，活性调节靶性肌肉衍生的神经营养因子的产生（合成或释放）（例如，活性丧失会增加产生的产生，从而挽救运动神经元）。第三个新的假设提出，活性阻断通过神经营养因子独立途径挽救了运动神经元。提出了三个特定的目的，以检查这些替代方案的每一种（但不一定是相互排斥的）解释依赖于活动的MN存活。在第一个目的中，将在活体活性扰动后，将在肌肉和神经中测定神经营养因子的表达（mRNA，蛋白质）。在第二个目标中，将检查细胞粘附分子介导的活性扰动后肌内轴突分支的变化。在第三个目标中，将检查细胞内第二信号信号通路，以确定活性扰动后神经营养因子介导的运动神经元生存中是否涉及不同的分子机制。总的来说，拟议的研究提供了新的方法来阐明体内活动依赖性运动神经元生存的机制，这将促进我们对发育神经元死亡的理解。他们还具有通过揭示神经肌肉活性改变的方法来扩大我们对病理运动神经元死亡的概念的潜力。