This project is dedicated to discovering ways to induce regeneration of the corticospinal tract (CST) and recovery of motor function after spinal cord injury (SCI). The CST is the pathway that is responsible for the ability to move voluntarily. Damage to the CST as a result of a spinal cord injury is the reason people are paralyzed. The present project is based on recent extraordinary discoveries that the CST can be induced to regenerate following spinal cord injury by targeting molecular pathways that control cell growth in development, specifically phosphatase and tensin inhibitor (PTEN). PTEN is responsible for shutting down the type of protein synthesis that is critical for cell growth during development. PTEN acts by blocking the mammalian target of rapamycin, (mTOR), so deletion of PTEN releases inhibition on mTOR, which in turn allows the cell to synthesize proteins that are critical for cell growth. Importantly, the same molecular pathways are also the key to allowing neurons to regenerate their axons following injury. Based on this, recent studies have shown that genetic deletion of PTEN in mice allows neurons to mount a robust regenerative response. Most critically, our studies demonstrate that when PTEN is deleted in neurons in the cerebral cortex, the neurons that give rise to the CST are able to robustly regenerate their axons after SCI. The fact that regeneration of the CST can be successfully induced provides us with an unprecedented opportunity to address a question that is central to regeneration research-whether it is possible to induce regeneration in a therapeutically-relevant time frame and whether inducing CST regeneration is enough to restore circuits of sufficient specificity to allow some degree of restoration of motor function. The project uses anatomical and physiological methods to assess the degree to which regenerated axons grow along normal tracts, to normal targets, form functional synapses, and contribute to motor function. Pre-clinical experiments will also assess whether it is possible to down-regulate PTEN in a therapeutically-relevant time frame and using non-genetic interventions.

Public Health Relevance

This project builds upon the novel discovery that axon regeneration can be induced following spinal cord injury by targeting molecular pathways that control cell growth during development. The project will assess whether it is possible to target these molecular pathways in a therapeutically relevant time frame and whether the regeneration is sufficient to restore motor function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS073857-01A1
Application #
8238106
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
2011-08-15
Project End
2016-05-31
Budget Start
2011-08-15
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$334,688
Indirect Cost
Name
University of California Irvine
Department
Type
Organized Research Units
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Steward, Oswald; Willenberg, Rafer (2017) Rodent spinal cord injury models for studies of axon regeneration. Exp Neurol 287:374-383
Sharp, Kelli G; Duarte, Jaime E; Gebrekristos, Berkenesh et al. (2016) Robotic Rehabilitator of the Rodent Upper Extremity: A System and Method for Assessing and Training Forelimb Force Production after Neurological Injury. J Neurotrauma 33:460-7
Steward, Oswald (2016) A Rhumba of ""R's"": Replication, Reproducibility, Rigor, Robustness: What Does a Failure to Replicate Mean? eNeuro 3:
Gutilla, Erin A; Steward, Oswald (2016) Selective neuronal PTEN deletion: can we take the brakes off of growth without losing control? Neural Regen Res 11:1201-3
Gutilla, Erin A; Buyukozturk, Melda M; Steward, Oswald (2016) Long-term consequences of conditional genetic deletion of PTEN in the sensorimotor cortex of neonatal mice. Exp Neurol 279:27-39
Pirbhoy, Patricia Salgado; Farris, Shannon; Steward, Oswald (2016) Synaptic activation of ribosomal protein S6 phosphorylation occurs locally in activated dendritic domains. Learn Mem 23:255-69
Willenberg, Rafer; Zukor, Katherine; Liu, Kai et al. (2016) Variable laterality of corticospinal tract axons that regenerate after spinal cord injury as a result of PTEN deletion or knock-down. J Comp Neurol 524:2654-76
Kwon, Brian K; Streijger, Femke; Hill, Caitlin E et al. (2015) Large animal and primate models of spinal cord injury for the testing of novel therapies. Exp Neurol 269:154-68
Blanc, Caroline A; Grist, Jonathan J; Rosen, Hugh et al. (2015) Sphingosine-1-phosphate receptor antagonism enhances proliferation and migration of engrafted neural progenitor cells in a model of viral-induced demyelination. Am J Pathol 185:2819-32
Willenberg, Rafer; Steward, Oswald (2015) Nonspecific labeling limits the utility of Cre-Lox bred CST-YFP mice for studies of corticospinal tract regeneration. J Comp Neurol 523:2665-82

Showing the most recent 10 out of 22 publications