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Multi-dimensional plasma proteomic profiling elucidates molecular mechanisms and pathophysiological networks in
Enis Cela1, David Tweddell2, Mark Daley2,3
1Physiology & Pharmacology, Western University, London, ON, N6A 3K7, Canada.
Insights
This study identified 65 plasma proteins and pathways linked to pediatric severe traumatic brain injury (sTBI) severity and outcomes. Interleukin-6 (IL-6) was a key protein, suggesting new diagnostic and therapeutic targets for sTBI.
Area of Science:
- Neuroscience
- Biochemistry
- Genomics
Background:
- Severe traumatic brain injury (sTBI) significantly impacts pediatric mortality and morbidity.
- Heterogeneous sTBI progression complicates prognosis and investigation.
- Advanced approaches are needed to understand pediatric sTBI.
Purpose of the Study:
- To identify plasma protein alterations specific to pediatric sTBI.
- To uncover functional pathways correlating with clinical variables in pediatric sTBI.
- To advance understanding of sTBI pathophysiology beyond traditional methods.
Main Methods:
- Plasma proteomic analysis of 20 pediatric sTBI patients and controls.
- Quantification of 1,472 proteins using proximity extension assays.
- Gene set enrichment analysis for pathways and Gene Ontology terms.
Main Results:
- Identified 65 differentially expressed proteins (FDR-adjusted P < 0.05, FC ≥ 4).
- Found proteins involved in neuroinflammation and cytokine/receptor signaling pathways.
- Observed correlations between pathways and injury severity, hyperglycemia, and coagulopathy.
Conclusions:
- Identified novel plasma proteins and pathways associated with pediatric sTBI clinical features.
- Highlighted IL-6 as a central hub protein, suggesting prognostic and therapeutic potential.
- Demonstrated the utility of proteomic profiling for understanding pediatric sTBI and informing precision medicine.
Background:
Severe traumatic brain injury (sTBI) is a leading cause of trauma-related mortality and morbidity in pediatric populations. The heterogeneous progression of sTBI presents significant challenges for prognosis and pathophysiological investigation, necessitating advances beyond traditional approaches. This study utilized plasma proteomic profiling to identify sTBI-specific protein alterations and functional pathways correlating with clinical variables in pediatric patients.
Methods:
We performed plasma proteomic analysis on 20 matched pairs of pediatric sTBI patients and healthy controls. Proximity extension assays quantified 1,472 proteins. Gene set enrichment analysis identified enriched Reactome pathways and Gene Ontology terms among differentially expressed proteins. Pathway-clinical variable associations were calculated using weighted correlation sums between pathway proteins and clinical variables. Protein-protein interaction networks were analyzed using STRING.
Results:
Using significance thresholds of FDR-adjusted P < 0.05 and fold change ≥ 4, we identified 65 differentially expressed proteins between sTBI samples and controls. Analysis revealed proteins involved in neuroinflammation and upregulated pathways related to cytokine and receptor/ligand signaling. Altered protein expression indicated structural and functional changes in neurons, glial cells, and vasculature. Upregulated pathways positively correlated with injury severity score, hyperglycemia, and coagulopathy, while negatively correlating with vault skull fractures and acidosis. IL-6 emerged as a central hub in protein-protein interactions, with distinct clusters representing opsonization, TNF family signaling, amidation, neuronal/astrocyte injury, and multifaceted sTBI responses.
Conclusions:
These findings identify differentially expressed plasma proteins and enriched signaling pathways associated with clinical features, providing novel insights into pediatric sTBI pathophysiology. The identification of IL-6 as a central hub protein and the correlation of specific pathways with injury severity, metabolic dysfunction, and coagulopathy suggest potential targets for therapeutic intervention and prognostic biomarker development. This proteomic approach advances our understanding of the complex molecular cascades underlying pediatric sTBI and may inform precision medicine strategies for improved patient outcomes.
