The long-term objective of this researchis to understand the mechanisms underlying the unmasking of latent motor pathways which restore function to muscle paralyzed by spinal cord injury. An animal model of spinal cord injury and plasticity known as the """"""""crossed phrenic phenomenon"""""""" (CPP) is employed to demonstrate that a latent respiratory motor pathway can be activated to restore function to a hemidiaphragm paralyzed by an ipsilateral C2 spinal cord hemisection. Based on new information, a neurotransmitter mediated neuronal-glial interaction may be partially responsiblefor the unmasking of the latent pathway. In addition, the development of two pharmacological methods of activating the latent pathway may lead to improvement of respiratory muscle function not only in our animal model, but also in cervical spinal cord injured humans. There are four specific aims in the present application to test the following hypotheses: 1. that the delayed enhanced expression of the CPPis dependent on serotonin. 2. that serotonin depletion blocks or attenuates the rapid alterations in astrocyte morphology which may be important in the delayed enhanced expression of the CPP. 3. that continuous infusion of a glutamate metabotropic receptor agonist into the subarachnoid space near the medullary chemoreceptor center will not only induce, but also chronically maintain recovery of a hemidiaphragm previously paralyzed by cervical spinal cord injury. 4. that either oral or intravenously administered theophylline will significantly improve respiratory muscle function following cervical spinal cord injury in man.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD031550-27
Application #
7447433
Study Section
Special Emphasis Panel (NSS)
Program Officer
Nitkin, Ralph M
Project Start
1993-08-01
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2011-05-31
Support Year
27
Fiscal Year
2008
Total Cost
$302,124
Indirect Cost
Name
Wayne State University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Zhang, Yanhua; Walker, Janelle Buttry; Minic, Zeljka et al. (2016) Transporter protein and drug-conjugated gold nanoparticles capable of bypassing the blood-brain barrier. Sci Rep 6:25794
Minic, Zeljka; Zhang, Yanhua; Mao, Guangzhao et al. (2016) Transporter Protein-Coupled DPCPX Nanoconjugates Induce Diaphragmatic Recovery after SCI by Blocking Adenosine A1 Receptors. J Neurosci 36:3441-52
Beth Zimmer, M; Grant, Joshua S; Ayar, Angelo E et al. (2015) Ipsilateral inspiratory intercostal muscle activity after C2 spinal cord hemisection in rats. J Spinal Cord Med 38:224-30
Buttry, Janelle L; Goshgarian, Harry G (2015) WGA-Alexa transsynaptic labeling in the phrenic motor system of adult rats: Intrapleural injection versus intradiaphragmatic injection. J Neurosci Methods 241:137-45
Buttry, Janelle L; Goshgarian, Harry G (2014) Injection of WGA-Alexa 488 into the ipsilateral hemidiaphragm of acutely and chronically C2 hemisected rats reveals activity-dependent synaptic plasticity in the respiratory motor pathways. Exp Neurol 261:440-50
Goshgarian, Harry G; Buttry, Janelle L (2014) The pattern and extent of retrograde transsynaptic transport of WGA-Alexa 488 in the phrenic motor system is dependent upon the site of application. J Neurosci Methods 222:156-64
Nantwi, Kwaku D (2009) Recovery of respiratory activity after C2 hemisection (C2HS): involvement of adenosinergic mechanisms. Respir Physiol Neurobiol 169:102-14
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Goshgarian, Harry G (2009) The crossed phrenic phenomenon and recovery of function following spinal cord injury. Respir Physiol Neurobiol 169:85-93
Huang, Yonglu; Goshgarian, Harry G (2009) The potential role of phrenic nucleus glutamate receptor subunits in mediating spontaneous crossed phrenic activity in neonatal rat. Int J Dev Neurosci 27:477-83

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