Lesioned spinal cord long-tract axons can grow into a lesion/graft site if growth factors are locally provided. Separately, intraganglionic elevation of cAMP can promote dorsal column sensory sprouting after spinal cord lesions. However, achieving host axonal growth beyond cell grafts placed in spinal cord lesion sites has proven difficult, yet will likely be required for functionally meaningful recovery after SCI. Recently, we succeeded in promoting axonal regeneration into and beyond sites of cervical SCI using a combinatorial approach of: 1) cAMP stimulation of the neuronal soma, 2) autologous cell bridges in the lesion site, and 3) growth factor gradients provided as stimuli to axons in and beyond the lesion site. Controls lacking all three of these treatments did not exhibit bridging. This project will further develop this approach, identify its mechanistic underpinnings, and reduce it to potential clinical practicality. The following specific aims will be pursued:
Specific Aim 1 : Determine whether a combinatorial approach to regeneration will promote axonal regeneration and functional recovery after spinal cord lesions.
Specific Aim 2 : Determine whether a combinatorial approach to regeneration will promote tissue sparing, axonal regeneration and functional recovery after acute spinal cord contusions.
Specific Aim 3 : Determine whether a combinatorial approach to regeneration will promote axonal regeneration and functional improvement after chronic spinal cord contusions. The UCSD Center for Neural Repair also has in place primate SCI models for proof-of-concept testing of these findings, allowing potential reduction to practicality. We further have a track record of responsibly translating promising therapies from the bench to bedside.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049881-05
Application #
7418223
Study Section
Special Emphasis Panel (ZNS1-SRB-R (06))
Program Officer
Kleitman, Naomi
Project Start
2004-08-03
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$537,876
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nielson, Jessica L; Haefeli, Jenny; Salegio, Ernesto A et al. (2015) Leveraging biomedical informatics for assessing plasticity and repair in primate spinal cord injury. Brain Res 1619:124-38
Lu, Paul; Woodruff, Grace; Wang, Yaozhi et al. (2014) Long-distance axonal growth from human induced pluripotent stem cells after spinal cord injury. Neuron 83:789-96
Tuszynski, Mark H; Steward, Oswald (2012) Concepts and methods for the study of axonal regeneration in the CNS. Neuron 74:777-91
Nout, Yvette S; Rosenzweig, Ephron S; Brock, John H et al. (2012) Animal models of neurologic disorders: a nonhuman primate model of spinal cord injury. Neurotherapeutics 9:380-92
Nout, Yvette S; Ferguson, Adam R; Strand, Sarah C et al. (2012) Methods for functional assessment after C7 spinal cord hemisection in the rhesus monkey. Neurorehabil Neural Repair 26:556-69
Blesch, Armin; Lu, Paul; Tsukada, Shingo et al. (2012) Conditioning lesions before or after spinal cord injury recruit broad genetic mechanisms that sustain axonal regeneration: superiority to camp-mediated effects. Exp Neurol 235:162-73
Lu, Paul; Blesch, Armin; Graham, Lori et al. (2012) Motor axonal regeneration after partial and complete spinal cord transection. J Neurosci 32:8208-18
Lu, Paul; Wang, Yaozhi; Graham, Lori et al. (2012) Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150:1264-73
Gros, Thomas; Sakamoto, Jeff S; Blesch, Armin et al. (2010) Regeneration of long-tract axons through sites of spinal cord injury using templated agarose scaffolds. Biomaterials 31:6719-29
Rosenzweig, Ephron S; Courtine, Gregoire; Jindrich, Devin L et al. (2010) Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nat Neurosci 13:1505-10

Showing the most recent 10 out of 14 publications