The role of nerve growth factor-related neurotrophins as survival factors during development is now well established. The neurotrophins also have great potential to regulate neurons in adulthood and thus may serve as potent therapeutic agents. Because neurotrophin-3 (NT-3) supports proprioceptive neurons, it is anticipated that NT-3 will be effective in the treatment of disorders that involve large myelinated sensory fibers. The long-term objective is to characterize the cellular and molecular actions of NT-3 on postnatal primary sensory neurons to understand how NT-3 may improve sensory impairment. The proposed studies will focus on two paradigms that compromise proprioceptive neurons: peripheral nerve injury and neuronal degeneration in disease. Three animal models, NT-3 transgenic, NT-3 null mutant, and hereditary mutant mice that undergo degeneration of NT-3-dependent proprioceptive neurons will be studied. With this approach, the trophic support of neurons following perturbation can be characterized in vivo, and NT-3 transgenes can be introduced into other mouse models to test the therapeutic effects of- NT-3. The first Specific Aim will characterize the interactions between injured proprioceptive neurons and their 5 trophic support at different stages postnatally.
This Aim will then test if NT-3 stimulates proprioceptive axons to regenerate, branch, and reinnervate targets in muscle.
The second Aim will examine the role of NT-3 in the degeneration of proprioceptive neurons in dystonia musculorum (dst) mice, a mouse model for sensory ataxia.
This Aim will then test the therapeutic potential of NT-3 by breeding a muscle-expressed NT-3 transgene into dst mice. Finally, this Aim will explore how the disruption of newly-identified genes in dst mice cause the selective vulnerability of proprioceptive neurons. Results from these studies will define new biological actions of NT-3 and reveal how manipulation of the trophic support of neurons may be useful to treat pathologic neural conditions.
