Injuries to the brachial plexus result in the reduction or loss of use of the upper extremities due to damage to the brachial nerves and/or spinal roots. These injuries are usually the result of vehicle accidents or falls. Peripheral nerve grafts have been increasingly effective in restoring some motor and sensory function when only peripheral nerves are damaged or broken. Repair of damaged spinal roots is less successful, however, especially in restoring sensory function after damage or avulsion (breakage) of dorsal roots, which are the pathway of sensory axons from the periphery to the spinal cord. Sensory axons can regenerate within the root itself but do not cross into the spinal cord. When sensory input from the limb is drastically reduced or eliminated in this way, there are life-long disabilities for the injured person. The experiments proposed in this application are designed to develop potential therapies to restore sensory function after damage to dorsal roots. Several neurotrophic factors are already known to promote anatomical and functional regeneration of sensory fibers after dorsal root crush. Artemin, a member of the glial-derived neurotrophic factor family of neurotrophins, is especially effective in promoting the functional regeneration of both large, proprioceptive and small, nociceptive sensory axons after root crush. Artemin will be tested for its ability to restore specific and persistent sensory function following crush injuries of brachial dorsal roots in adult rats. Recovery of sensory function will be assessed using anatomical, behavioral and electrophysiological techniques. In a related project, a method for promoting regeneration after dorsal root avulsion will be developed. Many brachial root injuries result in complete breakage of the roots from the spinal cord (avulsions) rather than partial damage. In these cases, sensory axons must be guided back to the spinal cord before regeneration can occur. The cut ends of avulsed sensory roots will be surgically reattached to the spinal cord and treated with artemin to determine if sensory function can be restored. The goal of these experiments is to determine if artemin is sufficiently effective to warrant study for the repair of brachial root injuries in humans.

Public Health Relevance

The goal of this project is to develop an effective treatment for injuries that cause loss of sensory function in the arms and legs. These injuries are due to damage to spinal roots, where the nerves connect to the spinal cord, and they seriously impair the injured person's ability to use his/her limbs. We will test one promising therapeutic agent that promotes recovery of sensory function in rats to determine its effectiveness in re-establishing functional connections between damaged sensory nerves and their normal targets in the spinal cord. The knowledge gained from these experiments will accelerate human clinical testing of this and other potential therapies. Short version of Public Health Relevance Statement (24 words): A protein promoting sensory nerve regrowth after nerve damage in rats will be tested for its effectiveness in restoring appropriate and lasting sensory function. Revised Check Boxes Section There are no changes in any of the check boxes concerning human embryonic stem cells, human subject coding, or Phase 3 clinical trials. None of these boxes should be checked.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Kleitman, Naomi
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Tufts University
Schools of Medicine
United States
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Wong, Laura Elisabeth; Gibson, Molly E; Arnold, H Moore et al. (2015) Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush. Proc Natl Acad Sci U S A 112:6170-5
Smith, George M; Falone, Anthony E; Frank, Eric (2012) Sensory axon regeneration: rebuilding functional connections in the spinal cord. Trends Neurosci 35:156-63
Harvey, Pamela; Gong, Bangjian; Rossomando, Anthony J et al. (2010) Topographically specific regeneration of sensory axons in the spinal cord. Proc Natl Acad Sci U S A 107:11585-90
Harvey, Pamela A; Lee, Daniel H S; Qian, Fang et al. (2009) Blockade of Nogo receptor ligands promotes functional regeneration of sensory axons after dorsal root crush. J Neurosci 29:6285-95