Our long-term goal is to develop treatments for acute and chronic spinal cord injury (SCI) that can be translated into clinical care. The combination of therapeutic interventions, such as transplantation and exercise (EX), can lead to reorganization of the spinal cord, as shown by anatomical, physiological and behavioral assays. Our Projects will address the general areas of regeneration and activity dependent plasticity after SCI, focusing on transplant-mediated effects on recovery of function and the proposition that exercise will facilitate further recovery by promoting connectivity of regenerating axons at local and/or distant sites. Project 1 will provide a mechanistic examination of the effects of activity dependent or transplant dependent changes in the spinal cord microenvironment on regenerating axons as signified by changes in intra-axonal signaling. Project 2 will focus on the benefits offered by transplantation of neural restricted precursor cells (neuronal and glial) after adult rat SCI. Basic mechanisms by which stem cells promote neuroprotection, long distance axonal growth, relay of information across a lesion and support recovery of function will be explored. Project 3 will use spinalized rats to address mechanisms of transplant and EX-mediated reorganization of spinal cord circuitry. Whether activity-dependent plasticity creates an environment more conducive to axonal regeneration will be determined. These studies then will be advanced into a cat model of SCI. Project 4 will use spinalized cats to test whether transplant-derived neurotrophins modify excitability of afferent pathways during locomotion and whether locomotor circuitry can be re-engaged in a chronic injury paradigm. Throughout the Projects multiple injury models, combinations of treatments to promote repair and study of acute vs. chronic treatment will be used to explore the potential for functional recovery. The Administration Core will monitor research progress through weekly meetings of PPG participants, will review changes in research design initiated by project results and foster project interactions. The Behavior and Biomechanics Core will conduct established behavioral assessments of SCI animals to specify the effects of lesions and treatments and to provide insights into recovery mechanisms. The Cell and Molecular Biology Core will provide stem cells, modified fibroblasts and viral vectors for transplantation and assist Projects with PCR and protein assays. The Histology Core will prepare tissue sections for tract tracing and immunocytochemical reactions and perform image analysis of transplant-mediated axonal regeneration and sprouting. The Surgery Core will instruct Projects with procedures of transplantation in SCI animals. The Electrophysiology Core will provide training and support in techniques necessary to demonstrate functional connectivity and recovery after SCI. This Program Project has direct relevance to the design and implementation of future treatment programs for acute and delayed intervention after SCI.

Public Health Relevance

Neural tissue and cell transplantation and exercise will be tested for efficacy in promoting regeneration after spinal cord injury. We will explore when a treatment might be most effective by delaying treatment for weeks to months after injury. This approach directly impacts the overwhelming number of chronically injured spinal cord injured patients. In a preclinical study we will pursue studies in a large animal model, spinal cord injured cats, examining the potential to promote structural and functional recovery after an acute or chronic injury and the ability to foster greater recovery through aggressive physical rehabilitation training. We feel that results of this study will have direct clinical relevance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS055976-06A1
Application #
8475801
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Jakeman, Lyn B
Project Start
2006-07-01
Project End
2018-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$1,271,929
Indirect Cost
$446,928
Name
Drexel University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Twiss, Jeffery L; Fainzilber, Mike (2016) Neuroproteomics: How Many Angels can be Identified in an Extract from the Head of a Pin? Mol Cell Proteomics 15:341-3
Detloff, Megan Ryan; Quiros-Molina, Daniel; Javia, Amy S et al. (2016) Delayed Exercise Is Ineffective at Reversing Aberrant Nociceptive Afferent Plasticity or Neuropathic Pain After Spinal Cord Injury in Rats. Neurorehabil Neural Repair 30:685-700
Sachdeva, Rahul; Farrell, Kaitlin; McMullen, Mary-Katharine et al. (2016) Dynamic Changes in Local Protein Synthetic Machinery in Regenerating Central Nervous System Axons after Spinal Cord Injury. Neural Plast 2016:4087254
Jin, Y; Bouyer, J; Shumsky, J S et al. (2016) Transplantation of neural progenitor cells in chronic spinal cord injury. Neuroscience 320:69-82
Sachdeva, Rahul; Theisen, Catherine C; Ninan, Vinu et al. (2016) Exercise dependent increase in axon regeneration into peripheral nerve grafts by propriospinal but not sensory neurons after spinal cord injury is associated with modulation of regeneration-associated genes. Exp Neurol 276:72-82
Yuan, Xiao-bing; Jin, Ying; Haas, Christopher et al. (2016) Guiding migration of transplanted glial progenitor cells in the injured spinal cord. Sci Rep 6:22576
Twiss, Jeffery L; Kalinski, Ashley L; Sachdeva, Rahul et al. (2016) Intra-axonal protein synthesis - a new target for neural repair? Neural Regen Res 11:1365-1367
Hayakawa, Kazuo; Haas, Christopher; Fischer, Itzhak (2016) Examining the properties and therapeutic potential of glial restricted precursors in spinal cord injury. Neural Regen Res 11:529-33
Jin, Ying; Bouyer, Julien; Haas, Christopher et al. (2015) Evaluation of the anatomical and functional consequences of repetitive mild cervical contusion using a model of spinal concussion. Exp Neurol 271:175-88
Hayakawa, Kazuo; Haas, Christopher; Jin, Ying et al. (2015) Glial restricted precursors maintain their permissive properties after long-term expansion but not following exposure to pro-inflammatory factors. Brain Res 1629:113-25

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