Grants We Funded

Abstract
Severe peripheral nerve injuries often leave patients with longstanding pain, paralysis and numbness. Longer distances to the target end organs produce worse outcomes. We have recently found that a novel strategy of side-to-side nerve grafting leads to improved regeneration: conducting very small numbers of fibers from an intact donor nerve to an adjacent injured recipient nerve results in enhanced regeneration of the recipient nerve. Very few axons are required to enter the recipient denervated nerve stump to exert the protective effect, suggesting that soluble chemical mediators are likely to play a role. The overarching hypothesis of this proposal is that donor axons sustain the growth permissive state of Schwann cells (SC) in the denervated stump. We will assess this hypothesis by testing the following sub-hypotheses: 1. The protective effect of side-to-side nerve grafts increases with the number of grafts, and that bridging axons regenerate both proximally and distally within the recipient injured nerve. We will use our novel transgenic rats whose axons fluoresce to examine whether the axons regenerate both proximally and distally within the recipient injured nerve. We will also examine using retrograde labeling of neurons the relationship between number of grafts and the magnitude of the protective effect. 2. Locally produced soluble factors from regenerating axons promote SC differentiation and/or proliferation, thus mediating protection of chronically denervated stumps. We will examine whether leading candidate molecules produced by neurons including calcitonin gene related peptide and neuregulin are the prime mediators of protection by blocking their actions with siRNA in vivo. This discovery will likely alter the paradigm by which surgeons will reconstruct devastating proximal injuries. Clinical use of the technique will be optimized by detailed knowledge of its mechanism.