Despite timely and meticulous surgical reconstruction, recovery following proximal traumatic peripheral nerve injuries is often poor. Muscles that are denervated for over a year are characterized by fibrosis and loss of motor end plates and cannot be effectively reinnervated even when regenerating axons reach their motor targets. Agents capable of increasing the rate of axonal regeneration and appropriately directing regenerating motor axons down motor paths and sensory axons down sensory paths after injury have been sought to optimize recovery from peripheral nerve injuries. The exogenous administration of neurotrophic factors and neuroimmunophilin ligands have demonstrated variable neuroregenerative efficacy. Glial-derived neurotrophic factor (GDNF) is an especially potent motor neuron survival factor that has shown some benefit in recovery following peripheral nerve injury. However, the effects of GDNF on the rate and specificity (motor vs. sensory) of axonal regeneration, the importance of its route of administration, and its mechanism of action have not been rigorously tested in clinically relevant peripheral nerve injury paradigms. To address these issues, we have developed two distinct lines of transgenic mice with well-characterized patterns of GDNF overexpression in the central nervous system or peripheral muscle. In addition, these mice express enhanced yellow fluorescent protein in most of their motor and sensory axons or green fluorescent protein in only a few peripheral motor nerves to enable serial tracking of nerve regeneration. In our specific aims we use these murine models to study the neuroenhancing effects of central or peripheral GDNF overexpression following nerve injury.
In aims 1 a and 1b, the neuroregenerative effects of central or peripheral GDNF overexpression are compared between proximal and distal peripheral nerve crush and repaired transection injuries both morphologically and functionally. We will also study GDNF-mediated downstream signaling pathways and GDNF-mediated transcriptional regulation involved in nerve regeneration.
In aim 2 a the neuroenhancing effects of GDNF overexpression from central and peripheral sources are evaluated in transection injuries repaired in an acute or delayed fashion with nerve grafts or end- to-side repair.
In aim 2 b we study the additive effects of GDNF and FK506 on nerve regeneration both histologically and mechanistically following end-to-end repair of sciatic nerve transection injury. In addition to establishing the route of GDNF delivery, peripheral- or central-, that will most effectively stimulate regeneration after peripheral nerve injury, in aim 3 we utilize our transgenic model to study preferential motor reinnervation - a concept with extreme clinical relevance to peripheral nerve surgeons. We will determine which source of trophic support, target- or pathway-derived has the most influence in directing regenerating axons to their appropriate targets. ? ? ?

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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Washington University
Schools of Medicine
Saint Louis
United States
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Wang, Ze Zhong; Sakiyama-Elbert, Shelly E (2018) Matrices, scaffolds & carriers for cell delivery in nerve regeneration. Exp Neurol :
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Ee, Xueping; Yan, Ying; Hunter, Daniel A et al. (2017) Transgenic SCs expressing GDNF-IRES-DsRed impair nerve regeneration within acellular nerve allografts. Biotechnol Bioeng 114:2121-2130
Marquardt, Laura M; Sakiyama-Elbert, Shelly E (2015) GDNF preconditioning can overcome Schwann cell phenotypic memory. Exp Neurol 265:1-7
Hoben, Gwendolyn; Yan, Ying; Iyer, Nisha et al. (2015) Comparison of acellular nerve allograft modification with Schwann cells or VEGF. Hand (N Y) 10:396-402
Marquardt, Laura M; Ee, Xueping; Iyer, Nisha et al. (2015) Finely Tuned Temporal and Spatial Delivery of GDNF Promotes Enhanced Nerve Regeneration in a Long Nerve Defect Model. Tissue Eng Part A 21:2852-64
Wood, Matthew D; Mackinnon, Susan E (2015) Pathways regulating modality-specific axonal regeneration in peripheral nerve. Exp Neurol 265:171-5
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
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

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