Neuromuscular junction regeneration

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The long term goal of our study is to understand mechanisms underlying functional recovery from muscle and nerve injuries. In this proposal we will focus on regeneration of the neuromuscular junction (NMJ). The NMJ is a synapse that transmits signals from motor neurons to muscle fibers to control muscle contraction. Skeletal muscle and peripheral nerve injuries are common among soldiers in non-battle related activities such as exercise. Their incident rate increases significantly during war time. In fact, extremity injuries account for the majority of combat wounds. Unavoidably, the NMJ becomes damaged in skeletal muscle and peripheral nerve injuries. In addition, muscles become denervated in various peripheral neurodegenerative disorders like amyotrophic lateral sclerosis, Duchenne-Aran muscular atrophy and progressive bulbar palsy, many of which affect veterans more than the general population. Recovery from muscle/nerve injuries and peripheral neurodegenerative disorders requires nerve regrowth, muscle repair and in particular NMJ regeneration, a process by which denervated muscles become reinnervated by motor nerves. However, unlike nerve and muscle repair/regeneration, much less is known about molecular mechanisms of reinnervation of injury muscles, which is a glaring gap in our understanding of functional recovery from muscle/nerve injury. Consequently, therapeutic interventions to promote NMJ regeneration are limited. Recent studies have revealed critical mechanisms for NMJ assembly and maintenance. Evidence indicates that the agrin signaling is not only important for NMJ formation, but also necessary for its maintenance. These advances provide a niche to study mechanisms of NMJ regeneration. In this proposal, we will test the hypotheses that agrin signaling is critical for NMJ regeneration after injury and that increasing agrin signaling promotes NMJ regeneration. The results will provide a better understanding of agrin signaling in NMJ regeneration, a prerequisite to developing better therapeutic intervention for muscle/nerve injury from combat wounds and peripheral neurological disorders that occur at higher rates among veterans.