Integrated systems analysis reveals conserved gene networks underlying response to spinal cord injury

Spinal cord injury (SCI) is a devastating neurological condition for which there are currently no effective treatment options to restore function. A major obstacle to the development of new therapies is our fragmentary understanding of the coordinated pathophysiological processeses triggered by damage to the human spinal cord. An additional challenge to translation of preclinical therapies is the reliance of clinical trials on standardized neurological assessments to enrol and stratify patients, rather than objective injury biomarkers. Here, we describe a systems biology approach to integrate decades of small-scale experiments with unbiased, genome-wide gene expression from the human spinal cord, revealing a gene regulatory network signature of the pathophysiological response to SCI. Our integrative analyses converge on an evolutionarily conserved gene subnetwork enriched for genes associated with the response to SCI by small-scale experiments, and whose expression is upregulated in a severity-dependent manner following injury and downregulated in functional recovery. We validate the severity-dependent upregulation of this subnetwork in prospective transcriptomic and proteomic studies. Our analysis provides a systems-level view of the coordinated molecular processes activated in response to SCI. Further, our results nominate quantitative biomarkers of injury severity and functional recovery, with the potential to facilitate development and translation of novel therapies. Examination of rat spinal cord transcriptome after spinal cord injuries of different severities; The T9 spinous process was identified and a laminectomy was performed to expose the T10 spinal segment. Following this the animal was transferred to the IH impactor stage, where the T8 and T10 spinous processes were securely clamped using modified Allis forceps. The animal was stabilized on the platform and the impactor tip (2.0 mm) was properly aligned using a 3-dimensional coordinate system moving platform. The position of the impactor was confirmed as midline by two separate experimenters. The IH system was set to deliver an impact of 0 (control), 100, or 200 kdyn of pre-defined force.