Spinal cord injury (SCI) results in the loss of many functions, of which motor disability is undoubtedly the more commonly recognized neurological outcome. Especially devastating are injuries that commonly occur in the cervical region of the spinal cord. At those levels SCI affects not only upper and lower extremity movements, but also impairs one of the more basic functions required for survival - namely, respiration. There is a high incidence of respiratory complications following cervical SCI, which can occur even when assisted ventilation is not required. Furthermore, respiratory dysfunction and associated secondary complications remain the leading cause of morbidity and mortality in people with cervical SCI. Particularly concerning is that the number of cervical SCIs has increased in recent years. Although optimal spinal cord repair has yet to be achieved, there is mounting experimental and clinical evidence for some spontaneous functional recovery - or plasticity - over time post-injury. However, the extent of improvement that can be attributed to plasticity remains limited. Results from our recent experiments have demonstrated that transplantation of stem-like cells at the site of injury can enhance anatomical repair and improve diaphragm function following clinically-relevant cervical SCI. The diaphragm is regarded as the primary muscle of respiration. The experiments proposed here build upon our extensive experience with respiratory outcomes following cervical SCI, and will test whether maturing donor nerve cells can anatomically and functionally integrate with spinal circuits responsible for diaphragm activity. These experiments will also employ a novel optogenetic approach to control the activity of transplanted cells and test whether the functionality can be enhanced between donor neurons and the injured host spinal cord. Not only will these experiments test a promising treatment approach in an important and clinically relevant injury model, but they will significantl improve our understanding of the therapeutic potential of a wide range of neuronal transplantation approaches, including many of the stem cell therapies currently being tested experimentally and clinically.

Public Health Relevance

While it has long been thought that spinal cord injuries resulted in permanent paralysis, research has shown that a small amount of recovery - called plasticity - can occur naturally as the injured spinal cord attempts to rebuild itself. Although th extent of recovery is limited, treatments that strengthen this plasticity will likely lead to the bst therapeutic outcomes. Accordingly, the present research program will test whether transplanting healthy neurons can provide the building blocks to form new neuronal pathways capable of enhancing plasticity and improve recovery.

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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Jakeman, Lyn B
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Drexel University
Anatomy/Cell Biology
Schools of Medicine
United States
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Spruance, Victoria M; Zholudeva, Lyandysha V; Hormigo, Kristiina M et al. (2018) Integration of Transplanted Neural Precursors with the Injured Cervical Spinal Cord. J Neurotrauma 35:1781-1799
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Hormigo, Kristiina M; Zholudeva, Lyandysha V; Spruance, Victoria M et al. (2017) Enhancing neural activity to drive respiratory plasticity following cervical spinal cord injury. Exp Neurol 287:276-287
Bezdudnaya, Tatiana; Marchenko, Vitaliy; Zholudeva, Lyandysha V et al. (2017) Supraspinal respiratory plasticity following acute cervical spinal cord injury. Exp Neurol 293:181-189
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