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.
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