Several different therapeutic approaches have produced significant recovery of motor function in experimental models of spinal cord injury (SCI). These treatments include strategies designed to enhance axon regeneration and strategies targeted towards remyelination, tissue sparing and training the spared circuits. Their potential usefulness at the bedside, however, is critically dependent on nerve-muscle connectivity that not only remains functional but also functions as efficiently as possible. Surprisingly, however, the synaptic responses of muscles to SCI have received little attention, and the neuromuscular junctions (NMJs) caudal to SCI are assumed to remain intact. Our preliminary morphological analyses, however, suggest that NMJs in hindlimb muscles of adult rats paralyzed by SCI may be extremely dysfunctional. Furthermore, these studies imply that adult NMJs may be extraordinarily diverse and specific in their sensitivity to paralysis. In this R21 application, we will use fluorescent transgenic mice, in vivo time-lapse imaging, and combined electrophysiological and morphological analyses to determine (1) if there are multiple subpopulations of NMJs that differ in pre- and postsynaptic sensitivity to the SCI-elicited paralysis, and (2) if physiologically significant loss of nerve-muscle connectivity accompanies morphological instability of NMJs distal to SCI. These results will provide critical data to justify a larger grant application to: explore the molecular mechanisms underlying the unexpected diversity of mature NMJs;comprehensively assess the contribution of NMJ loss to motor deficits associated with SCI;and attempt to promote motor recovery by stabilizing NMJs. The proposed work therefore has the potential to establish a strong foundation for developing novel treatments for spinal cord injured patients.

Public Health Relevance

Several different therapeutic approaches have produced significant recovery of motor function in experimental models of spinal cord injury. These treatments include strategies designed to enhance axon regeneration and strategies targeted towards remyelination, tissue sparing and training the spared circuits. The project seeks to provide a novel basis for motor deficits and recovery following spinal cord injury by identifying nerve-muscle connections, termed neuromuscular junctions, as novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS062320-02
Application #
7657402
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
2008-09-01
Project End
2010-12-31
Budget Start
2009-09-01
Budget End
2010-12-31
Support Year
2
Fiscal Year
2009
Total Cost
$30,063
Indirect Cost
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kim, Young-Phil; Lee, Gil-Su; Kim, Jong-Wan et al. (2015) Phosphate glass fibres promote neurite outgrowth and early regeneration in a peripheral nerve injury model. J Tissue Eng Regen Med 9:236-46
Skuba, Andrew; Manire, Meredith Ann; Kim, Hyukmin et al. (2014) Time-lapse in vivo imaging of dorsal root nerve regeneration in mice. Methods Mol Biol 1162:219-32
Je, H Shawn; Yang, Feng; Ji, Yuanyuan et al. (2013) ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions. J Neurosci 33:9957-62
Joo, Na-Young; Knowles, Jonathan C; Lee, Gil-Su et al. (2012) Effects of phosphate glass fiber-collagen scaffolds on functional recovery of completely transected rat spinal cords. Acta Biomater 8:1802-12
Ramirez, Servio H; Haskó, János; Skuba, Andrew et al. (2012) Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci 32:4004-16
Han, Seung Baek; Kim, Hyukmin; Skuba, Andrew et al. (2012) Sensory Axon Regeneration: A Review from an in vivo Imaging Perspective. Exp Neurobiol 21:83-93
Ferguson, Toby A; Son, Young-Jin (2011) Extrinsic and intrinsic determinants of nerve regeneration. J Tissue Eng 2:2041731411418392
Lin, Shen; Liu, Mei; Son, Young-Jin et al. (2011) Inhibition of Kinesin-5, a microtubule-based motor protein, as a strategy for enhancing regeneration of adult axons. Traffic 12:269-86
Hanna, Amgad S; Son, Young-Jin; Dempsey, Robert (2011) Live imaging of dorsal root regeneration and the resurgence of a forgotten idea. Neurosurgery 69:N18-21
Di Maio, Alessandro; Skuba, Andrew; Himes, B Timothy et al. (2011) In vivo imaging of dorsal root regeneration: rapid immobilization and presynaptic differentiation at the CNS/PNS border. J Neurosci 31:4569-82

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