Surgical repair of injured peripheral nerve often fails to restore adequate function. Misdriction of regenerating axons is a primary cause of this failure. Motor axons reaching skin provide no function and block the pathways which they occupy; cutaneous axons reaching muscle may function, but will provide incorrect information. Recent experiments suggest a possible solution to this problem. Motor axons regenerating in the rat femoral nerve produce multiple collaterals sprouts; motor/sensory specificity is improved by pruning collaterals from cutaneous nerve while keeping those in muscle nerve. Specificity may be enhanced by crushing the nerve before repair to increase collateral sprout formation and pathway sampling. If a similar effect could be produced at the time of nerve suture, the outcome of clinical nerve repair could be substantially improved. The proposed experiments are designed to further characterize the process of specificity generation through collateral pruning, and to identify techniques for its amplification which could be applied to clinical nerve repair.
Aim I more clearly defines the mechanism by which nerve crush increases specificity, and seeks to correlate increased specificity with improved function.
Aim II seeks to stimulate regenerative collateral sprouting of motor axons and subsequent regeneration specificityby application of trophic factors directly the repair site in a controlled manner. The function resulting from these manipulations will be correlated with regeneration specificity. These experiments open the way to direct clinical application of specificity enhancement.
Aim III takes advantage of the greater specificity observed in juveniles to gain further insights into the mechanism of motor/sensory specificity, and introduces a novel nerve graft model which confornts adult pathways with juvenile axons and vice versa, to identify components which deteriorate with age. The extent of collateral sprouting in juvenile and aged rats will be correlated with final regeneration specificity.
Aim I V Evidence for pruning of motor axon collaterals from cutaneous nerve has been obtained with axon tracing techniques. These experiments will seek morphologic and electrophysiologic confirmation of pruning.
Aim V extends our observations of specific motor pathway characteristics to compare motor and sensory nerve as graft for regenerating motor axons. Preliminary experiments suggest that motor nerve is in fact superior, a finding which if confirmed will have immediate, direct clinical relevance.
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