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Discovery of Lipidome Alterations Following Traumatic Brain Injury via High-Resolution Metabolomics

ABSTRACT: Traumatic brain injury (TBI) can occur across wide segments of the population, presenting in a heterogeneous manner that makes diagnosis inconsistent and management challenging. Biomarkers offer the potential to objectively identify injury status, severity, and phenotype by measuring the relative concentrations of endogenous molecules in readily accessible biofluids. Through a data-driven, discovery approach, novel biomarker candidates for TBI were identified in the serum lipidome of adult male Sprague-Dawley rats in the first week following moderate controlled cortical impact (CCI). Serum samples were analyzed in positive and negative ion modes by Ultra Performance Liquid Chromatography Mass Spectrometry (UPLC-MS). A predictive panel for the classification of injured and uninjured sera samples, consisting of 26 dysregulated species belonging to a variety of lipid classes, was developed with a cross-validated accuracy of 85.3% using omniClassifier software to optimize feature selection,. Polyunsaturated fatty acids (PUFAs) and PUFA-containing diacylglycerols were found to be upregulated in sera from injured rats, while changes in sphingolipids and other membrane phospholipids were also observed, many of which map to known secondary injury pathways. Overall, the identified biomarker panel offers viable molecular candidates representing lipids that may readily cross the blood brain barrier (BBB) and aid in the understanding of TBI pathophysiology.

INSTRUMENT(S): QTOF

ORGANISM(S): Rat Rattus Norvegicus

TISSUE(S): Blood

DISEASE(S): Brain Injury

SUBMITTER: Scott Hogan

PROVIDER: ST000920 | MetabolomicsWorkbench | Fri Jan 19 00:00:00 GMT 2018

REPOSITORIES: MetabolomicsWorkbench

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Project description:Abstract Background Traumatic brain injury (TBI) results in irreversible damage at the site of impact and initiates cellular and molecular processes that lead to secondary neural injury in the surrounding tissue. We used microarray analysis to determine which genes, pathways and networks were significantly altered using a rat model of TBI. Adult rats received a unilateral controlled cortical impact (CCI) and were sacrificed 24h post-injury. The ipsilateral hemi-brain tissue at the site of the injury, the corresponding contralateral hemi-brain tissue, and naM-CM-/ve (control) brain tissue were used for microarray analysis. Ingenuity Pathway Analysis (IPA) software was used to identify molecular pathways and networks that were associated with the altered gene expression in brain tissues following TBI. Results Inspection of the top fifteen biological functions in IPA associated with TBI in the ipsilateral tissues revealed that all had an inflammatory component. IPA analysis also indicated that inflammatory genes were altered on the contralateral side, but many of the genes were inversely expressed compared to the ipsilateral side. The contralateral gene expression pattern suggests a remote anti-inflammatory molecular response. We created a network of the inversely expressed common (i.e., same gene changed on both sides of the brain) inflammatory response (IR) genes and those IR genes included in pathways and networks identified by IPA that changed on only one side. We ranked the genes by the number of direct connections each had in the network, creating a gene interaction hierarchy (GIH). Two well characterized signaling pathways, toll-like receptor/NF-kappaB signaling and JAK/STAT signaling, were prominent in our GIH. Conclusions Bioinformatic analysis of microarray data following TBI identified key molecular pathways and networks associated with neural injury following TBI. The GIH created here provides a starting point for investigating therapeutic targets in a ranked order that is somewhat different than what has been presented previously. In addition to being a vehicle for identifying potential targets for post-TBI therapeutic strategies, our findings can also provide a context for evaluating the potential of therapeutic agents currently in development. The ipsilateral hemi-brain tissue at the site of the injury, the corresponding contralateral hemi-brain tissue, and naM-CM-/ve (control) brain tissue (n=3 for each) were used for RNA isolation. The TBI injured animals were Todd 1, 2 Todd, and Todd 3, each yielding an ispilateral and contralateral sample. The naM-CM-/ve animals were Xu 13 control, Xu 2 control, and Xu 6 control.

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Discovery of Lipidome Alterations Following Traumatic Brain Injury via High-Resolution Metabolomics

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