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 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 orend- 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. Wewill determine which source of trophic support, target- or pathway-derived has the most influence in directing regenerating axons to their appropriate targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051706-05
Application #
7755025
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
2006-08-15
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$365,201
Indirect Cost
Name
Washington University
Department
Surgery
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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; 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
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
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
Johnson, P J; Wood, M D; Moore, A M et al. (2013) Tissue engineered constructs for peripheral nerve surgery. Eur Surg 45:
Marquardt, Laura M; Sakiyama-Elbert, Shelly E (2013) Engineering peripheral nerve repair. Curr Opin Biotechnol 24:887-92

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