Proteomic portraits of human and porcine spinal cord injury define cross-species biomarkers of injury severity and recovery
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ABSTRACT:
INSTRUMENT(S): Agilent 6550 LC-MS/MS, 6490 Triple Quadrupole LC/MS
ORGANISM(S): Sus Scrofa (ncbitaxon:9823) Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Dr. Brian K. Kwon
PROVIDER: MSV000085567 | MassIVE | Tue Jun 09 17:04:00 BST 2020
SECONDARY ACCESSION(S): PXD019685
REPOSITORIES: MassIVE
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Project description: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.
2018-09-25 | PXD010192 | Pride
Project description: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.
2018-10-02 | GSE115067 | GEO
Project description:Spinal cord injury (SCI) is one of the most disabling health problems facing adults today. Locomotor training has been shown to induce substantial recovery in muscle size and muscle function in both transected and contusion injury animal models of SCI. The overall objective of this study is to implement genome wide expression profiling of skeletal muscle to define the molecular pathways associated with muscle remodeling after SCI and during locomotor training (TM). We profiled rat soleus of total 36 samples including controls; 3, 8 and 14 days after SCI; 8 and 14 days after SCI with locomotor treadmill training (TM).
2015-06-30 | E-GEOD-45550 | biostudies-arrayexpress
Project description:Traumatic spinal cord injury (SCI) may induce irreversible damage leading to severe incapacity. Molecular mechanisms underlying SCI are not fully understood, preventing the development of novel therapeutic resources. Tamoxifen has demonstrated to be a promising therapy. Our aim was to elucidate the molecular mechanisms involved in the beneficial effect of TMX administered after SCI. We use a rat model of SCI, Tamoxifen was administred intraperitoneal 30 min after injury. Four groups were organized, 1) Non-injured without TMX (Sham/TMX-), 2) Non-injured with TMX (Sham/TMX+), 3) Injured without TMX (SCI/TMX-), and 4) Injured with TMX (SCI/TMX+). From the comparison between Sham/TMX- and SCI/TMX-, 708 genes showed differential expression. Among the relevant genes Anxa1 was upregulated, this gene’s product is a promising marker of injury severity. Enriched pathways were the spinal cord injury pathway and pathways related to inflammatory response. When comparing SCI/TMX- versus SCI/TMX+, only 30 genes showed differential expression. Our results reinforce the key role of inflammatory response in SCI and Tamoxifen seem to be able to regulate this response by suppressing changes in gene expression. Our data also support the potential of previously described severity markers.
2023-09-14 | GSE229618 | GEO
Project description:Spinal cord injury (SCI) is one of the most disabling health problems facing adults today. Locomotor training has been shown to induce substantial recovery in muscle size and muscle function in both transected and contusion injury animal models of SCI. The overall objective of this study is to implement genome wide expression profiling of skeletal muscle to define the molecular pathways associated with muscle remodeling after SCI and during locomotor training (TM).
2015-06-30 | GSE45550 | GEO
Project description:Aims: To better understand the potential mechanisms of hyperbaric oxygen (HBO) treatment alleviating spinal cord injury (SCI). Materials and methods: The SCI model was firstly built in mice, which were randomly divided into three groups: Sham (SH), SCI and HBO groups, followed by hind limb motor function evaluation. Then the spinal cord tissue samples were harvested for genome-wide transcriptional analysis at 1 week after injury. Finally, some highly expressed lnc-rna were selected for functional analysis. Results: the present study uncovered the lncRNAs expression profile of spinal cord following HBO treatment, and identified 577 DE lncRNAs in spinal cord sample among the SH, SCI and HBO groups. The key biological process and pathways were also identified and may be important mechanisms by which HBO treatment alleviating SCI Conclusions: Moreover, this study indicated that lncRNAs NONMMUT 092674.1 and NONMMUT042986.2 may be involved in the process of HBO treatment promoting the recovery of neurological function after SCI.
2022-03-24 | GSE199043 | GEO
Project description:Purpose: 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. Method Part1: A total of 27 female C57BI/6J mice (10-16 weeks of age; 20-25g; The Jackson Laboratory, Bar Harbor, ME) were used with 9 mice in each of following groups: shame control, 2 and 7 days after SCI. The surgical procedure for SCI were described previously [PMID:23289019]. Briefly, after anesthetization with a mixed solution of ketamine (80 mg/kg, ip) and xylazine (10 mg/kg, ip), mice received a dorsal laminectomy at the 9th thoracic vertebral (T9) level to expose the spinal cord and then a moderate T9 contusive injury using an Infinite Horizons impactor (PrecisionSystems and Instrumentation) at 60 kdyn with the spinestabilized using steel stabilizers inserted under the transverse processes one vertebra above and below the injury [PMID:19196178] . The shame control mice received only a dorsal laminectomy without contusive injury. Afterwards, the wound was sutured in layers, bacitracin ointment(Qualitest Pharmaceuticals,Huntsville, AL) was applied tothe wound area, 0.1mL of a 20 mg/ml stock of gentamicin(ButlerSchein, Dublin, OH) was injected subcutaneously, and the animals recovered on a water-circulating heating pad. Then mice received analgesic agent, buprenorphin(0.05 mg/kg, SQ; Reckitt Benckise, Hull, England)twice a day for two days. Bladders were manually expressed until automatic voiding returned spontaneously, which generally was within 7 days. At 2 or 7 days after SCI, the mice were anesthetized again with ketamine and xylazine and perfused briefly with normal physical saline. The injured spinal cords were then dissected and three 0.5 mm pieces of spinal cord were cut in the injured epicenter. All spinal cords were immediately frozen in liquid nitrogen and processed for RNA isolation. The spinal cords from three mice were combined into one biological replicate for RNA extraction. Three biological replicates were used. Method Part2: RNA-Seq was performed on the polyadenylated fraction of RNA isolated from tissue samples of acute (2D) and subacute phase (7D) and normal tissues (control, denoted as CTR hereafter). Three biological replicates were used for each phase.150-300 ng total RNAs were used for each sequencing library. RNA samples were polyA selected and paired-end sequencing libraries were constructed using TruSeq RNA Sample Prep Kit as described in the TruSeq RNA Sample Preparation V2 Guide (Illumina).The samples were then sequenced using the Illumina HiSeq sequencer. More than 30 million 100bp paired-end reads were generated from each biological replicate. Method Part3: Read mapping and Transcriptome construction were done by using optimized pipeline which integrate Tophat followed by Cufflinks. Result: 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. Conclusion: in this study we have described an example of how global gene profiling can be translated to screening genes of interest 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. mRNA profiles of Acute/subacute phase Spinal Cord Injury sample from mice were generated by RNA-sequencing using Illumina HiSeq.
2013-08-22 | E-GEOD-45376 | biostudies-arrayexpress
Project description:Background: Chronic spinal cord injury (SCI) remains one of the most debilitating neurological disorders and the majority of SCI patients are in the chronic phase. Previous studies of SCI that were limited by resources and technology have usually focused on few genes and pathways at a time. Thus, a comprehensive view of the complex molecular changes underlying SCI pathophysiology is needed. In particular, the biological roles of long non-coding RNAs (lncRNAs), a class of regulatory RNAs, have never been characterized systemically in SCI. Results: This study is the first to investigate alterations in the expression of both coding and long non-coding genes in the sub-chronic and chronic stages of SCI using RNA-Sequencing. Our data revealed differentially expressed genes, canonical pathways, and networks unique to particular time points or common to multiple time points in the progression of SCI. For example, a network of multiple critical genes responsible for astrogliosis and fibrosis was identified among differentially expressed genes common to three time points (1month, 3months, and 6 months after SCI). Moreover, the potential functions of rat lncRNAs in SCI were extensively analyzed. First, a comprehensive annotation database was compiled for rat lncRNAs that revealed several interesting characteristics of lncRNAs in the rat genome. Then, by correlating the temporal expression patterns of lncRNAs with those of protein-coding genes, we identified lncRNAs that are associated with functional categories such as signaling pathways, immune response, epigenetic modification, nervous system, and extracellular matrix. The expression patterns of some lncRNAs are highly correlated with those of their most proximal protein-coding genes, so it is possible that these lncRNAs regulate the expression of their protein-coding neighbors. Finally, we searched for transcription factor motifs enriched in the upstream regulatory regions of differentially expressed lncRNAs, and identified differentially expressed lncRNAs that are homologous to human genomic regions harboring molecular variants associated with human neurological diseases. Conclusions: Overall, our study provides an unprecedented resource for the study of sub-chronic and chronic SCI that will help the research community identify new molecular targets for future functional investigation.
2017-01-07 | GSE93249 | GEO
Project description:Spinal cord injury (SCI) is a severe neurological dysfunction, and its pathogenesis remains inadequately understood. Here, to spatiotemporally decode the cellular and molecular pathogenesis of SCI, we performed spatial transcriptomics analysis of 12,930 single cells from 21 samples of SCI contusion model mice. We identified the specific cellular subtypes, differentially expressed genes (DEGs), cell signaling networks, site-specific genes (SSGs), and transcription factors involved in SCI. Our analysis indicated that fibroblasts served as the hub of intracellular communication in the SCI site, sent continuous immune signals to neurocytes, and induced the other cell types to express high levels of the fibroblast marker gene Col1a2. Pseudotime analysis visualized trajectories that emerged from fibroblasts, passed through microglia and ended at neurons after SCI. When the proportion of fibroblasts and their cellular communications were attenuated by solu-medrol treatment, the BMS and MEP performance of SCI mice increased significantly; moreover, the ratio of Col1a2+ cells decreased markedly, and a new subtype of fibroblasts expressing Arg1 appeared. Our results highlight the vital pathological position of fibroblasts and indicate it as a significant therapeutic target for SCI.
2022-11-27 | GSE190910 | GEO
Project description:Astrocytes are taking the center stage in neurotrauma and neurological disease as they appear to play a dominant role in the inflammatory processes associated with these conditions. Previously, we reported that inhibiting nuclear factor kappa B (NF-kB) activation in astrocytes, by using a transgenic mouse model (GFAP-IκBα-dn mice), results in improved functional recovery following spinal cord injury (SCI), with increased white matter preservation and axonal sparing. In the present study we sought to determine whether this improvement, due to inhibiting NF-k-B activation in astrocytes, could be the result of enhanced oligogenesis in our GFAP-IκBα-dn mice. To gain insight into the underlying molecular mechanisms, we performed microarray analysis in naïve and 3 days, 3 and 6 weeks following SCI in GFAP-IκBα-dn and wild type (WT) littermate mice. Surprisingly, we found the largest number of genes differentially regulated between GFAP-IκBα-dn and WT mice 6 weeks post-injury. Interestingly, the data suggested that inhibiting astroglial NF-kB alters the inflammatory environment to support oligogenesis. Furthermore, confirmation of microarray data with qPCR and western blotting analysis and using BrdU labeling along with cell specific immunohistochemistry, confocal microscopy and quantitative cell counts, we demonstrate a significant increase in oligogenesis in GFAP-IκBα-dn following SCI. These studies suggest that therapeutic strategies targeting NF-kB activation in the CNS following SCI may promote oligogenesis and remyelination. Wild type (WT) mice - time points naïve, 3 days, 3 weeks, 6 weeks. Transgenic mice (TG) - time points naïve, 3 days, 3 weeks, 6 weeks.
2013-09-01 | E-GEOD-46695 | biostudies-arrayexpress