Combinatorial approach to restore breathing after spinal cord injury

PROJECT SUMMARY / ABSTRACT More than half of human spinal cord injury (SCI) cases occur at the cervical level, resulting in permanent respiratory deficits for which there is no treatment. Injury-induced axon growth of spared respiratory pathways is a form of endogenous neural plasticity that can be harnessed to improve breathing. However, experimental strategies to promote respiratory axon growth are lacking, and the few existing approaches have translational limitations. Without expanding the repertoire of molecular and/or cellular interventions to enhance axonal plasticity of the respiratory network following injury, developing treatment to restore breathing will be unlikely. The objectives of this proposal are: first, to determine if endogenous astrocytes can be reprogrammed to enhance structural plasticity of the respiratory system to improve breathing after SCI; and second, based on evidence that coupling axon growth-promoting strategy with rehabilitative training can further augment functional recovery, assess combinatorial effects of astrocyte reprogramming and respiratory training on recovery of breathing after SCI. The central hypothesis is that post-injury targeting of astrocytes, combined with respiratory training, will synergistically improve breathing after SCI. This hypothesis will be tested by pursuing two aims: 1) determine the effects of pre-injury astrocyte manipulation alone, or in combination with respiratory training, on structural and functional plasticity of the respiratory system; and 2) assess post-injury and location-specific effects of astrocyte manipulation alone, or in combination with respiratory training, on respiratory plasticity. The rationale for this proposal is that it will inform on the therapeutic potential of reprogramming endogenous astrocytes to promote axonal plasticity of the respiratory system, which may be further harnessed by rehabilitative training to maximize recovery of breathing after SCI.