Sex-specific Proteomic Signatures of the SUR1-TRPM4 Pathway in Plasma and Cerebrospinal Fluid after Severe Traumatic Brain Injury
Anupama Rani1, Shreya Satheesh3, Aurelia Cors4, Aditya Kumar2, Thomas Donovan5, Ethan Gaskin5, Semeon Afework2, Joshua Catapano6, Adam Eberle7, Sirin Gandhi2, Jane Hwang2, Kaitlyn Hebig2, Raemier Javelosa2, Erin McNally2, Margaux Miller2, Diana Monge Sanchez2, Nasathapot Namphol2, Felipe C. Albuquerque2, Andrew F. Ducruet2, Ashutosh P. Jadhav2, Michael T. Lawton2, Laura Snyder2, Patrick Kochanek5, Ruchira Jha2, Dhivyaa Rajasundaram5
1Department of Translational Neuroscience, Barrow Neurological Institute, 2Barrow Neurological Institute, 3Arizona State University, 4Yale University, 5University of Pittsburgh, 6University of Pennsylvania, 7Icahn School of Medicine
Objective:
To identify sex-specific plasma and/or cerebrospinal fluid (CSF) protein biomarkers within the Sulfonylurea-receptor-1(SUR1)—transient-receptor-potential-cation-channel-M-member-4 (TRPM4) pathway after traumatic brain injury (TBI).
Background:
We have previously demonstrated sex-specific differences in the SUR1-TRPM4 pathway impacting secondary injury processes and outcome after preclinical TBI. This remains unexplored in human patients but may have important implications for precision biomarkers and therapies.
Design/Methods:
We prospectively enrolled a cohort of ‘severe’-TBI patients with Glasgow Coma Scale (GCS) scores 3-8 and quantified 175 proteins in the SUR1-TRPM4 pathway in both plasma and CSF (TBI total=62, 48 plasma samples; control total=29, 15 plasma samples). T-tests with Benjamini-Hochberg correction identified differentially expressed proteins as an initial screen. Multivariate integrative sparse partial least squares discriminant analysis (MINT-sPLS-DA, R-mixOmics) identified the most discriminative proteins across sex and confirmed robustness. Functional enrichment analyses was performed with Gprofiler.
Results:
MINT-sPLS-DA identified 58 plasma proteins correlated with sex, discriminating between female vs male TBI patients. Proteins spanned multiple biological processes but predominantly impacted calcium-dependent/receptor signaling (p=5.3X10-8), immune cell proliferation (p=2.7X10-10) and several immune processes including response to IL6 (p=0.04), a known inflammatory mediator in TBI. 50% of sex-specific proteins overlapped with sex-specific responses in aneurysmal subarachnoid hemorrhage, although not always in the same direction. CSF samples were insufficient for sex-based analyses. Several identified proteins overlapped with markers of secondary injury (cerebral-edema, contusion-expansion) and discharge disposition (separate study) including IL6, KRAS, HMOX, AQP4, MMP9 among others.
Conclusions:
Sex-based differences in SUR1-TRPM4 pathway plasma proteins were noted post-TBI, several of which overlap with secondary injury associations. Validation of these markers may inform sex-based differences in underlying secondary injury mechanisms and potential precision-therapies post TBI.
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