Our ultimate goal is to develop effective strategies to improve outcome after human spinal cord injury (SCI). We have demonstrated (Pearse et al., 2004) that a triple combination of a SC implant, a one-time injection of cAMP into the cord above and below the implant, and a two-week subcutaneous infusion of Rolipram induced substantial growth of serotonergic fibers into the implant and beyond into the cord caudal to the implant. A marked improvement in locomotor test scores was observed in groups with the best growth of serotonergic axons in the caudal cord. To build on these results, we propose three Specific Aims using the same injury model and SC grafting (Pearse et al., 2004).
In Aim 1, we will determine the most effective delivery site (lesion, raphe somata, or both) for cAMP elevation (by measuring fibers and evaluating locomotion). BDNF is known also to promote growth of serotonergic axons into the cord caudal to a SC graft;therefore we will determine the most efficacious site for BDNF delivery using the same SCI paradigm.
In Aim 2, we propose to test the possibility that the combination of cAMP elevation and BDNF administration will be more effective than either one alone. Administration of cAMP (best route) and BDNF (best route) will be combined and the serotonergic axon growth response compared to that observed with either factor alone. Behavioral test results will be correlated with axon growth in each animal.
In Aim 3, we propose to determine the functionality of the serotonergic projections after our most effective treatment. First, changes in locomotion caused by pharmacologically blocking serotonergic receptors will be assessed. Second, we will determine reflex responses to somatic afferent stimulation following electrical stimulation of raphespinal pathways. Third, the release of 5-HT by descending fibers after the best treatment will be verified. Exploration of combined therapies to improve serotonergic fiber growth beyond the site of injury and determination of the role of the potentially improved growth on locomotion will lead to new clinical strategies in the future.

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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Owens, David F
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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Iorgulescu, J Bryan; Patel, Samik P; Louro, Jack et al. (2015) Acute Putrescine Supplementation with Schwann Cell Implantation Improves Sensory and Serotonergic Axon Growth and Functional Recovery in Spinal Cord Injured Rats. Neural Plast 2015:186385
Williams, Ryan R; Venkatesh, Ishwariya; Pearse, Damien D et al. (2015) MASH1/Ascl1a leads to GAP43 expression and axon regeneration in the adult CNS. PLoS One 10:e0118918
Williams, Ryan R; Henao, Martha; Pearse, Damien D et al. (2015) Permissive Schwann cell graft/spinal cord interfaces for axon regeneration. Cell Transplant 24:115-31
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Kanno, Haruo; Pressman, Yelena; Moody, Alison et al. (2014) Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. J Neurosci 34:1838-55
Flora, Govinder; Joseph, Gravil; Patel, Samik et al. (2013) Combining neurotrophin-transduced schwann cells and rolipram to promote functional recovery from subacute spinal cord injury. Cell Transplant 22:2203-17
Williams, Ryan R; Pearse, Damien D; Tresco, Patrick A et al. (2012) The assessment of adeno-associated vectors as potential intrinsic treatments for brainstem axon regeneration. J Gene Med 14:20-34
Ghosh, Mousumi; Tuesta, Luis M; Puentes, Rocio et al. (2012) Extensive cell migration, axon regeneration, and improved function with polysialic acid-modified Schwann cells after spinal cord injury. Glia 60:979-92
Ghosh, Mousumi; Garcia-Castillo, Daniela; Aguirre, Vladimir et al. (2012) Proinflammatory cytokine regulation of cyclic AMP-phosphodiesterase 4 signaling in microglia in vitro and following CNS injury. Glia 60:1839-59
Schaal, Sandra Marie; Garg, Maneesh Sen; Ghosh, Mousumi et al. (2012) The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury. PLoS One 7:e43634

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