The goal of this research is to improve the outcome of peripheral nerve repair. Our strategy is based on the discovery that regenerating motor axons preferentially reinnervate muscle and/or muscle nerve, a process termed Preferential Motor reinnervation (PMR). Previous experimental work suggested the pruning hypothesis: regenerating motor axons generate multiple collateral sprouts, which reinnervate previously sensory or motor Schwann cell tubes on a random basis. Over time, specific projections are generated by pruning collaterals from cutaneous pathways while maintaining those in muscle pathways. A motoneuron that initially samples both pathways is thus converted to one projecting to muscle. Motoneurons limited to cutaneous pathways have no means of correcting their error, and their number remains constant. Subsequent experiments evaluated the contributions of pathway and end organ to PMR. Naturally occurring variations in specificity were seen in response to both pathway age and neuronal age. This experimental finding correlated well with the clinical observation that peripheral nerve repair often restores normal function in young children but never does so in adults. Specificity could be manipulated by previous crush proximal to the site of nerve repair or by electrical stimulation for only one hour during the repair itself. The latter observation is exciting for two reasons:1) the increase in specificity was accompanied by a dramatic increase in regeneration speed, and 2) the technique is not only a research tool, but could be readily applied to clinical nerve repair without the need for implantation of a device or prolonged treatment. These experiments have evaluated the behavior of axon populations, defining the variables that modify regeneration specificity. The current proposal describes the next step in the progression from natural history observation to the formulation of treatment strategies: definition of the molecular basis of specificity generation. We have chosen the two variables with the greatest impact on the pathway (sensory vs. motor, predegeneration) and on the neuron (age, electrical stimulation), and will manipulate them to examine the molecular consequences for the pathway and neuron. Additional aims will further explore the mechanism and consequences of electrical stimulation, and evaluate the role of a motor pathway marker, the L2 carbohydrate, in specificity generation.
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