Motor axons can regenerate considerable distances through nerve trunk to reinnervate muscle, but terminal sprouting of intact nerve endings at innervated neuromuscular junctions (NMJ) to denervated junctions is clinically as important. Schwann cells appear to be essential for both axonal regeneration and terminal sprouting, but surprisingly little is known about the molecular basis of how Schwann cells do this. Neuronal cadherin (NCAD), a homophilic cell adhesion molecule expressed by both axons and Schwann cells is an attractive candidate to mediate axon growth. This idea will be critically tested by examining regeneration and terminal sprouting after genetically deleting NCAD in Schwanncells and/or motor axons in both cell culture and animal models of axon growth.
The specific aims will be: 1. To determine whether homophilic NCAD binding is required for neurite outgrowth.
In Aim 1 NCAD will be removed from Schwann cells or neurons in vitro and neurite growth measured;2. To determine whether NCAD is required for axonal regeneration, NCAD will be genetically deleted from Schwann cells or motor axons and regneration measured.
In Aim 2, NCAD will be removed from Schwann cells or motor axons using the Cre-lox system;3. To determine whether NCAD is required for neuromuscular junction reinnervation, terminal sprouting and NMJ reinnervation in mice lacking NCAD in Schwann cells or motor axons will be quantified.
In Aim 3 the mice from Aim 2 will be used but NMJ reinnervation and axon sprouting will be measured after partial denervation of muscle. The principal investigator has proposed a five-year period of supervised research and didactic training to transition to independence as a clinician and scientist. Steve Scherer, who has a long-standing interest and expertise in nerve regeneration, will supervise this research and serve as a model for management of both a scientific and clinical career. Rita Balice-Gordon will provide additional support and advice. The goal of the principal investigator is to become an independent, NIH-funded, scientist and clinician with recognized scientific expertise in nerve regeneration. The excellent academic environment and superb resources at the University of Pennsylvania will maximize the potential to succeed.
Peripheral nerve injury, both traumatic and disease-related, is common and recovery of strength and sensation is often poor. To better understand how cells within nerve promote recovery the principal investigator will determine if certain molecules found in nerve are critical for nerve growth. This knowledge will aid efforts to repair peripheral nerve after injury.
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| Kennerson, Marina L; Nicholson, Garth A; Kaler, Stephen G et al. (2010) Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet 86:343-52 |
