Abstract
Spinal cord injury (SCI) is a devastating neurological disease without effective treatment. To generate a comprehensive view of the mechanisms involved in SCI pathology, we applied RNA-Sequencing (RNA-Seq) technology to characterize the temporal changes in global gene expression after contusive SCI in mice. We sequenced tissue samples from acute and subacute phases (2 days and 7 days after injury) and systematically characterized the transcriptomes with the goal of identifying pathways and genes critical in SCI pathology. The top enriched functional categories include “inflammation response,” “neurological disease,” “cell death and survival” and “nervous system development.” The top enriched pathways include LXR/RXR Activation and Atherosclerosis Signaling, etc. Furthermore, we developed a systems-based analysis framework in order to identify key determinants in the global gene networks of the acute and sub-acute phases. Some candidate genes that we identified have been shown to play important roles in SCI, which demonstrates the validity of our approach. There are also many genes whose functions in SCI have not been well studied and can be further investigated by future experiments. We have also incorporated pharmacogenomic information into our analyses. Among the genes identified, the ones with existing drug information can be readily tested in SCI animal models. Therefore, in this study we have described an example of how global gene profiling can be translated to identifying genes of interest for functional tests in the future and generating new hypotheses. Additionally, the RNA-Seq enables splicing isoform identification and the estimation of expression levels, thus providing useful information for increasing the specificity of drug design and reducing potential side effect. In summary, these results provide a valuable reference data resource for a better understanding of the SCI process in the acute and sub-acute phases.
Highlights
Spinal cord injury (SCI) is one of the most debilitating neurological diseases
Moderate contusion SCI was used in the present study and the injury severity was confirmed by the histology staining and the locomotion test: Basso Mouse Score
Transcriptomes were reconstructed using our in-house pipeline. ~95% of all reads were mapped to the mouse reference genome (NCBI37/ mm9) and over 100 million reads were recognized as spanning a splice junction (Table S1)
Summary
Spinal cord injury (SCI) is one of the most debilitating neurological diseases. The expense associated with the medical care is very high, but clinically available treatments provide only modest benefit [2,3]. There are no effective treatments for this devastating neurological disorder. Previous studies indicated that in the acute phase of SCI, primary damage occurs as a direct result of trauma when resilience thresholds are surpassed, leading to immediate physical, biochemical and cellular alterations. Primary injury triggers multiple secondary injury cascades that cause further tissue loss and dysfunction [4]. Unraveling the detailed molecular events and especially the key genes and pathways would shed light on both understanding the injury mechanisms and developing therapeutic strategies
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