Muscle's role in regulating nerve terminal properties

这项应用的广泛目标是了解活动变化引起的肌肉变化在促进神经再支配和维持已建立的突触方面是如何重要的；并试图用基因疗法模拟活动诱导的变化。虽然已知神经末梢和肌肉相互作用来调节神经肌肉接头的结构和功能，但肌肉在这种相互作用中的作用仍然知之甚少。新的动物模型和基因治疗技术的出现使研究肌肉在促进和维持神经支配中的作用的新实验成为可能。提出了两个具体的目标：(1)确定肌肉在静止、失神经或再神经支配过程中的变化是否对维持或重建神经肌肉接头的正常结构和功能是必要的。两种新的疾病动物模型将被用于这项研究，目的是增加肌肉活动(在CLC-1小鼠中，失神经肌肉保持活跃)或降低肌肉活动(一种急性四肢瘫痪肌病模型，在该模型中，经皮质类固醇治疗的失神经肌肉变得不兴奋)。(2)通过将转录因子引入肌肉，直接诱导或防止肌肉失神经样变，是否可以改变神经肌肉接头的结构和功能。为此，含有肌生成素或阻断肌生成素活性因子的复制缺陷型腺病毒将被用来诱导或防止肌肉中基因表达的失神经样改变。将确定对成熟的和重新支配的神经肌肉接头的结构和功能的影响。拟议的实验将有助于确定如何操纵肌肉来改善运动神经元、神经、神经肌肉接头和肌肉疾病的神经肌肉接头的连接。

The broad objective of this application is to understand how changes in muscle induced by changes in activity are important in promoting reinnervation and maintaining established synapses; and to attempt to mimic activity-induced changes with gene therapy. Although it is known that nerve terminal and muscle interact to modulate structure and function of the neuromuscular junction, the role of muscle in this interaction remains poorly understood. The advent of new animal models and gene therapy technology have made possible new experiments to examine the role of muscle in promoting and maintaining innervation. Two specific aims are proposed: (1) to determine whether changes in muscle during inactivity, denervation or reinnervation are essential for maintenance or reestablishment of normal structure and function of the neuromuscular junction. Two new animal models of disease will be used in this aims to increase muscle activity (the Clc-1 mouse in which denervated muscle remains active) or decrease muscle activity (a model for acute quadriplegic myopathy in which denervated muscle treated with corticosteroids become inexcitable). (2) to determine whether introduction of transcription factors into muscle to directly induce or prevent denervation-like changes in muscle can alter neuromuscular junction structure and function. In this aim replication deficient adenoviruses containing either myogenin or factors that block activity of myogenin will be used to induce or prevent denervation-like changes of gene expression in muscle. The effect on structure and function of mature and reinnervated neuromuscular junctions will be determined. The proposed experiments will help determine ways in which to manipulate muscle to improve junction of the neuromuscular junction in diseases of motor neuron, nerve, neuromuscular junction and muscle.