Optimizing a Translational Strategy to Improve Breathing after SCI

Abstract Spinal cord injury at the high cervical level results in respiratory impairment. Activation of the latent respiratory pathway is an endogenous mechanism of neural plasticity that can contribute to restoration of breathing. We recently discovered that genetic stimulation of moderate astrocyte reactivity throughout the CNS via overexpression of leucine zipper-bearing kinase (LZK) in adult astrocytes enhances injury-induced CNS axon plasticity. Using this unique genetic model, we further found that stimulation of astrocyte reactivity improved recovery of breathing following high cervical lateral hemisection of the spinal cord. This pilot project will test the hypothesis that stimulation of astrocyte reactivity combined with intermittent hypoxia respiratory training will further augment activation of the latent pathway to enhance respiratory recovery. Additionally, local reactive astrocyte stimulation via AAV-mediated induction of astrocyte-targeted LZK expression at the level of phrenic nucleus will be tested as a therapeutic approach to recover breathing function after spinal cord injury.