Severe peripheral nerve injuries are common and result in significant long-term functional morbidity. Despite recent advances in the understanding of the neurobiology related to nerve regeneration and refinement in surgical techniques, complete functional recovery after repair is rare. Extended regeneration times and delayed surgical reconstruction are two major factors in poor functional recovery. Exogenous delivery of growth factors (GFs) has the potential to address both of these barriers. In particular, glial derived neurotrophic factor (GDNF) is a potent motor neuron survival factor that enhances motor axon regeneration after chronic nerve injury. It is known that delivery of GDNF in the periphery (i.e. skeletal muscle) and site of nerve injury has a positive impact on peripheral nerve regeneration. However, the parameters (location, timing, and duration) for appropriate administration of GDNF as a therapeutic intervention for peripheral nerve injury and its effects on Schwann cells (SCs) are unknown. The unifying hypothesis of this proposal is that appropriate spatial and temporal regulation of exogenous GDNF in distal nerve and muscle will enhance functional recovery following long gap chronic peripheral nerve injury. The current proposal combines a drug delivery system, and viral vector technology to sequentially increase the levels of GDNF along the path of regenerating axons;at the sight of injury, in the distal nerve, and denervated muscle. Temporary delivery of GDNF from a drug delivery system will be used to enhance levels at the sight of injury to support the initial phase of axonal regeneration. Early phase overexpression of GDNF from SCs (that can be repressed by tetracycline induced gene excision) will provide increased GDNF levels in the distal nerve in the middle phase of regeneration (without axonal trapping), and late phase tetracycline-induced GDNF expression in the muscle will stimulate reinnervation of the muscle after prolonged denervation. Additionally, the proposal will systematically evaluate how SCs, the major support cell of the peripheral nervous system, respond to increased levels of GDNF after nerve injury and their role in GDNF-enhanced nerve regeneration.
The aims of this proposal are: (1) To investigate the effect of spatially and temporally controlled GDNF using short term protein delivery at the site of injury and delayed, sequentially-induced delivery in the distal nerve and muscle to enhance recovery after chronic long nerve gap injury. (2) To determine the effect of increased GDNF levels on SCs and define their role in GDNF enhanced regeneration after peripheral nerve injury.

Public Health Relevance

In the United States alone, 360,000 people suffer from upper extremity nerve injuries annually, resulting in over 8.5 million restricted activity days and almos 5 million bed/disability days. The current approaches to nerve repairs result in suboptimal functional recovery. In this proposal, we seek to gain a better understanding of the environment factors that influence motor nerve regeneration in order to design specific therapies for patients with peripheral nerve injuries and improve their functional outcomes. The therapies developed in this study will target long gap and chronic nerve injuries, which have the poorest clinical outcomes and for which current therapies are inadequate.

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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Jakeman, Lyn B
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Washington University
Schools of Medicine
Saint Louis
United States
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Wu-Fienberg, Yuewei; Moore, Amy M; Marquardt, Laura M et al. (2014) Viral transduction of primary Schwann cells using a Cre-lox system to regulate GDNF expression. Biotechnol Bioeng 111:1886-94
Jesuraj, Nithya J; Santosa, Katherine B; Macewan, Matthew R et al. (2014) Schwann cells seeded in acellular nerve grafts improve functional recovery. Muscle Nerve 49:267-76
Jesuraj, Nithya J; Marquardt, Laura M; Kwasa, Jasmine A et al. (2014) Glial cell line-derived neurotrophic factor promotes increased phenotypic marker expression in femoral sensory and motor-derived Schwann cell cultures. Exp Neurol 257:10-8
Santosa, Katherine B; Jesuraj, Nithya J; Viader, Andreu et al. (2013) Nerve allografts supplemented with schwann cells overexpressing glial-cell-line-derived neurotrophic factor. Muscle Nerve 47:213-23
Marquardt, Laura M; Sakiyama-Elbert, Shelly E (2013) Engineering peripheral nerve repair. Curr Opin Biotechnol 24:887-92
Fox, Ida K; Mackinnon, Susan E (2011) Adult peripheral nerve disorders: nerve entrapment, repair, transfer, and brachial plexus disorders. Plast Reconstr Surg 127:105e-118e
Magill, Christina K; Moore, Amy M; Yan, Ying et al. (2010) The differential effects of pathway- versus target-derived glial cell line-derived neurotrophic factor on peripheral nerve regeneration. J Neurosurg 113:102-9
Kawamura, David H; Johnson, Philip J; Moore, Amy M et al. (2010) Matching of motor-sensory modality in the rodent femoral nerve model shows no enhanced effect on peripheral nerve regeneration. Exp Neurol 223:496-504
Magill, Christina K; Moore, Amy M; Borschel, Gregory H et al. (2010) A new model for facial nerve research: the novel transgenic Thy1-GFP rat. Arch Facial Plast Surg 12:315-20
Wood, Matthew D; Moore, Amy M; Hunter, Daniel A et al. (2009) Affinity-based release of glial-derived neurotrophic factor from fibrin matrices enhances sciatic nerve regeneration. Acta Biomater 5:959-68

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