This is a collaboration between experts at UCSD, UCLA, UCSF, UC Irvine, and UC Davis to examine plasticity and regeneration in the non-human primate spinal cord. Our goal is to enhance knowledge and translational relevance of research on spinal cord injury (SCI). Given findings of the last 5 years in this model, we focus this renewal on efforts to better understand and amplify the endogenous plasticity revealed in the primate system, and to test the translation of leading potential treatments discovered in non-primate models.
Aim 1 : Examine Electrophysiological and Anatomical Mechanisms Underlying Spontaneous Forelimb Functional Improvement After Primate SCI. Like humans, monkeys exhibit spontaneous improvement (but not full recovery) after C7 hemisection, and we have identified a remarkable degree of spontaneous sprouting of the primate corticospinal projection in association with this functional improvement.
Aim 1 will examine the time course of molecular, electrophysiological and systems-level (both corticospinal and non-corticospinal) mechanisms associated with behavioral improvement.
Aims 2 and 3: Test Candidate Therapies for Promoting Recovery The primate model of SCI is important not only for testing the efficacy of therapies discovered in rodents, but also for developing methods to deliver potential treatments to the larger primate system. We have tested several therapies in the last period of this grant, and plan to focus on new, promising approaches in the current grant period that target enhancement of plasticity and recovery. We will use the same techniques as in Aim 1 to examine the functional, electrophysiological, and anatomical consequences of the following:
Aim 2 : Chronic, Intermittent Stimulation with Cortically-Implanted Electrodes to Drive Plasticity of Spared Corticospinal Projections and Intraspinal Circuits.
Aim 3 : Chase Treatment after SCI.

Public Health Relevance

This research program will develop and test promising therapies for spinal cord injury in an animal model that could most closely predict human benefit. This is a collaborative endeavor between five research groups working closely together to accelerate discovery of therapies for human nervous system injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042291-12
Application #
8438429
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Ludwig, Kip A
Project Start
2011-08-15
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
12
Fiscal Year
2013
Total Cost
$1,129,108
Indirect Cost
$150,975
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
Rosenzweig, Ephron S; Brock, John H; Lu, Paul et al. (2018) Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat Med 24:484-490
Dulin, Jennifer N; Adler, Andrew F; Kumamaru, Hiromi et al. (2018) Injured adult motor and sensory axons regenerate into appropriate organotypic domains of neural progenitor grafts. Nat Commun 9:84
Kumamaru, Hiromi; Lu, Paul; Rosenzweig, Ephron S et al. (2018) Activation of Intrinsic Growth State Enhances Host Axonal Regeneration into Neural Progenitor Cell Grafts. Stem Cell Reports 11:861-868
Brock, J H; Rosenzweig, E S; Yang, H et al. (2018) Enhanced axonal transport: A novel form of ""plasticity"" after primate and rodent spinal cord injury. Exp Neurol 301:59-69
Patel, Akash; Li, Zhongzhi; Canete, Philip et al. (2018) AxonTracer: a novel ImageJ plugin for automated quantification of axon regeneration in spinal cord tissue. BMC Neurosci 19:8
Hunt, Matthew; Lu, Paul; Tuszynski, Mark H (2017) Myelination of axons emerging from neural progenitor grafts after spinal cord injury. Exp Neurol 296:69-73
Biane, Jeremy S; Takashima, Yoshio; Scanziani, Massimo et al. (2016) Thalamocortical Projections onto Behaviorally Relevant Neurons Exhibit Plasticity during Adult Motor Learning. Neuron 89:1173-1179
Sparrey, Carolyn J; Salegio, Ernesto A; Camisa, William et al. (2016) Mechanical Design and Analysis of a Unilateral Cervical Spinal Cord Contusion Injury Model in Non-Human Primates. J Neurotrauma 33:1136-49
Kadoya, Ken; Lu, Paul; Nguyen, Kenny et al. (2016) Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med 22:479-87
Lee-Kubli, Corinne A; Ingves, Martin; Henry, Kenneth W et al. (2016) Analysis of the behavioral, cellular and molecular characteristics of pain in severe rodent spinal cord injury. Exp Neurol 278:91-104

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