02-Sur1 Pathway Genetic Variability May Impact MMP9 Secretion, Ca2+ Signaling, ICP, and Outcome in TBI
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Neuroscience, 2021
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The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Benjamin Zusman


Introduction/Hypothesis: The Sur1-Trpm4 channel is a promising therapeutic target for cerebral edema and contusion expansion in traumatic brain injury (TBI), with an ongoing Phase-2 clinical trial of pharmacologic channel inhibition. We employed a bioinformatic approach to identify genetic contributors of Sur1-related pathways to secondary injury and outcome.

Methods: We used Ingenuity Pathway Analysis (IPA) to construct a pathway of genes potentially related to Sur1, and assessed exomic single nucleotide polymorphisms (SNPs)in a prospective cohort of severe TBI patients (N=386) using multiplex platforms. Phenotypes included intracranial pressure (ICP), contusion expansion (CE), and Glasgow Outcome Scale (GOS). We used stepwise regression models, controlling for multiple comparisons using the Benjamini-Yekutieli method. We identified biological processes and molecular functions using the Gene Ontology Knowledgebase.

Results: IPA identified 113 genes putatively contributing to the Sur1 pathway: 97 had analyzable variants, totaling 520 SNPs. 47 SNPs in 23 genes were associated with ICP, CE, or GOS after TBI (p-values: 5.9x10-3-8.0x10-9). Regulation of matrix metallopeptidase (MMP) secretion was the top biological process (Fold enrichment [FE]: >100, FDR = 0.008) and pattern recognition receptor activity was the top molecular function (FE: >100, FDR = 0.008). Among 16 genes associated with ICP, response to abiotic stimulus was the top biological process (FE: 8.88, FDR = 0.014). Catalase activity was the top molecular function (FE: >100, FDR = 0.036). In 6 genes associated with GOS, the top biological process was regulation of response to macrophage colony-stimulating factor (FE: >100, FDR = 0.004) and NAD(P)+ nucleosidase activity was the top molecular function (FE: >100, FDR = 0.013). No associations with CE were identified.

Conclusions: We identified genetic variability in biological processes that may contribute to differences in Sur1 related inflammation/Ca2+ signaling, ICP and outcome in TBI. This may help identify novel Sur1-related therapeutic targets. Regulation of MMP secretion was the top biologic process– this is consistent with the GAMES-RP trial findings, where Sur1 inhibition in stroke lowered plasma MMP9. Further defining individual variability in the Sur1 pathway may allow for targeted interventions.



Meta Tag
Content Type Presentation
Knowledge Area Neuroscience
Knowledge Level Advanced
Membership Level Select
Tag Traumatic Brain Injury TBI
Year 2021
genetic variants
SIR-1 pathway
traumatic brain injury
bioinformatics tools
intracranial pressure


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