Nerve injury compromises the function of over 80,000 Americans each year. Surprisingly, the treatment of nerve injury, surgical restoration of gross nerve continuity, has changed little in the last century. The discovery of factors that promote nerve regeneration has stimulated experimentation in a variety of animal models. In spite of this promising work, however, we still lack precise knowledge of which factors promote the regeneration of specific axon populations in vivo. This proposal extends work ongoing in our laboratory to provide this knowledge. We have shown that Schwann cells of myelinating peripheral nerve, once thought to express a single phenotype, vary widely in their growth factor expression. Furthermore, these specialized Schwann cells preferentially support the regeneration of their native axon population. We now propose to determine which of the factors expressed differentially in sensory and motor nerve are responsible for selective promotion of sensory and motor axon regeneration. Analysis will begin with correlation of growth factor concentration in various types of graft with their ability to promote sensory or motor regeneration. We have devised a novel technique of nerve repair in vitro that closely mimics repair in vivo, and will use this to observe the effects of augmenting or eliminating the function of specific factors. Schwann cells will then be modified in vivo to increase the expression of promising factors by transfecting them with lentiviral vectors or electroporating them with DNA plasmids. The most effective growth factors will be evaluated in the rat median nerve by measuring their impact on recovery of patterned and voluntary function after nerve grafting. Identification of the specific factors needed for optimal sensory and motor axon regeneration will have direct and immediate clinical implications for nerve repair, nerve grafting, and the use of Schwann cells to promote spinal cord regeneration.

Public Health Relevance

For over a century graft of cutaneous nerve has been used for neural reconstruction, often with poor results. Our recent work has shown that cutaneous and muscle nerves differ significantly in their growth factor production, and support regeneration on a modality-specific basis. The proposed experiments will determine which growth factors are responsible for this specificity, and will devise strategies for using these factors to improve the outcome of nerve repair and reconstruction, potentially helping thousands of patients a year.

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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Owens, David F
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Johns Hopkins University
Schools of Medicine
United States
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Wright, Megan C; Mi, Ruifa; Connor, Emmalynn et al. (2014) Novel roles for osteopontin and clusterin in peripheral motor and sensory axon regeneration. J Neurosci 34:1689-700
Siddique, Rezina; Vyas, Alka; Thakor, Nitish et al. (2014) A two-compartment organotypic model of mammalian peripheral nerve repair. J Neurosci Methods 232:84-92
Brushart, T M; Aspalter, M; Griffin, J W et al. (2013) Schwann cell phenotype is regulated by axon modality and central-peripheral location, and persists in vitro. Exp Neurol 247:272-81
Abdullah, M; O'Daly, A; Vyas, A et al. (2013) Adult motor axons preferentially reinnervate predegenerated muscle nerve. Exp Neurol 249:1-7
Vyas, Alka; Li, Zhaobo; Aspalter, Manuela et al. (2010) An in vitro model of adult mammalian nerve repair. Exp Neurol 223:112-8
Aspalter, Manuela; Vyas, Alka; Feiner, Jeffrey et al. (2009) Modification of Schwann cell gene expression by electroporation in vivo. J Neurosci Methods 176:96-103
Geremia, Nicole M; Gordon, Tessa; Brushart, Thomas M et al. (2007) Electrical stimulation promotes sensory neuron regeneration and growth-associated gene expression. Exp Neurol 205:347-59
Hoke, A; Redett, R; Hameed, H et al. (2006) Schwann cells express motor and sensory phenotypes that regulate axon regeneration. J Neurosci 26:9646-55
Eberhardt, Kirsten A; Irintchev, Andrey; Al-Majed, Abdulhakeem A et al. (2006) BDNF/TrkB signaling regulates HNK-1 carbohydrate expression in regenerating motor nerves and promotes functional recovery after peripheral nerve repair. Exp Neurol 198:500-10
Witzel, Christian; Rohde, Charles; Brushart, Thomas M (2005) Pathway sampling by regenerating peripheral axons. J Comp Neurol 485:183-90

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