Axonal Growth and Guidance for Nervous System Repair

Over 50,000 peripheral nerve repair procedures are performed a year due to injury (National Center for Health Statistics, 1995). These data do not include nerve injury due to tumor resection or prostatectomies. Even though the peripheral nerves regenerate well, only 10 to 20% of patients that undergo surgery to repair traumatic nerve injuries show excellent to very good recovery of function. The high incidence of failed recovery is due to the misrouting of regenerating axons to their targets. This proposal is designed to better understand the potential mechanisms that direct this growth to increase functional recovery in adults. The studies will examine the role strategically expressed neurotrophins and chemorepulsive factors will have on directing the growth of sensory and motor axons into appropriate nerve branches or the spinal cord. All the experiments in this proposal will use bioreabsorbale implants to induce nerve repair and targeted gene expression of guidance factors. The first aim of these experiments will expJore the use of the neurotrophins GDNF, BDNF, and NT-3 to induce the regeneration of sensory axon subsets across a 6mm dorsal root lesion gap and into the spinal cord. Behavioral analysis will examine recovery of mechanoreceptive and proprioceptiveresponses. The secondto forth aimof experimentswill use the femoralnerve model to examine . peripheral nerve targeting after large excision lesions to that nerve. The femoral nerve contains both sensory and motor axons that normally segregate into a sensory branch (saphenous) and a motor branch (quadriceps femoris). After cut injury, regeneration is mostly random, in which each branch will contain a mixture of both cutanteous sensory and motor axons. The second aim will be to guide sensory axons into the saphenous branch and not the motor branch. In this study, selective neurotrophins that are growth attractive for sensory axons will be expressed in the saphenous nerve and repulsive factors that are specifically inhibitory to sensory axons expressed in the motor branch. The third aim will examine neurotrophins and repulsive factors for the selective guidance of regenerating motor and proprioceptive axons into the motor branch and not the saphenous nerve. The forth aim is designed to incorporate the factors from aim 2 and 3 to optimize target directed regeneration to more normal like patterns. This aim will also develop and test clinically relevant bioreabsobable nerve cuffs for slow release of guidance factors. This grant proposal is designed to better define the molecular mechanisms that influence axonal regeneration and guidance within the adult PNS, with the ultimate goal of directing and organizing regeneration to more appropriate targets, while discouraging aberrant connections.