Abstract Details

Title Sex-specific Proteomic Signatures of the SUR1-TRPM4 Pathway in Plasma and Cerebrospinal Fluid after Severe Traumatic Brain Injury

Topic Neuro Trauma and Critical Care

Presentation(s) S21 - Neurocritical Care (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

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.

Authors/Disclosures
Anupama Rani, PhD PRESENTER	Dr. Rani has nothing to disclose.
Shreya Satheesh, Student	Ms. Satheesh has nothing to disclose.
Aurelia Cors	An immediate family member of Ms. Cors has received personal compensation in the range of $100,000-$499,999 for serving as a Office Director with US Environmental Protection Agency. An immediate family member of Ms. Cors has received personal compensation in the range of $100,000-$499,999 for serving as a Attorney with US Department of Justice.
Aditya Kumar, MD (Barrow Neurological Institute)	Dr. Kumar has nothing to disclose.
Thomas Donovan, MSc	Mr. Donovan has nothing to disclose.
Ethan Gaskin, MS	Mr. Gaskin has nothing to disclose.
Semeon Afework	Mr. Afework has nothing to disclose.
Joshua Catapano, MD	Dr. Catapano has nothing to disclose.
Adam Eberle	Mr. Eberle has nothing to disclose.
Sirin Gandhi, MD	Dr. Gandhi has nothing to disclose.
Jane Hwang	Ms. Hwang has nothing to disclose.
Kaitlyn Hebig	Ms. Hebig has nothing to disclose.
Raemier Javelosa	Ms. Javelosa has nothing to disclose.
Erin McNally, BS	Miss McNally has nothing to disclose.
Margaux Miller	Ms. Miller has nothing to disclose.
Diana L. Monge Sanchez, MD	Dr. Monge Sanchez has received research support from Barrow Neurological Foundation.
NASATHAPOT NAMPHOL, MD	Dr. NAMPHOL has nothing to disclose.
Felipe C. Albuquerque, MD	Dr. Albuquerque has nothing to disclose.
Andrew Ducruet, MD	Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kos. Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Phenox. Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Penumbra. Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Grace Therapeutics. The institution of Andrew Ducruet, MD has received research support from National Institute of Health.
Ashutosh P. Jadhav, MD, FAAN (Barrow Neurological Institute)	Dr. Jadhav has nothing to disclose.
Michael T. Lawton, MD	The institution of Dr. Lawton has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Zeiss. Dr. Lawton has received intellectual property interests from a discovery or technology relating to health care. Dr. Lawton has received personal compensation in the range of $500-$4,999 for serving as a Visiting Professor with Visiting Professor Honorariums.
Laura Snyder, MD	Dr. Snyder has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medtronic. Dr. Snyder has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Globus.
Patrick M. Kochanek, MD, MCCM (University of Pittsburgh)	Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for University of Washington. Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Johns Hopkins Health System. Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for de Boisblanc Law Firm. The institution of Patrick M. Kochanek, MD, MCCM has received research support from Chuck Noll Foundation. The institution of Patrick M. Kochanek, MD, MCCM has received research support from NIH. Patrick M. Kochanek, MD, MCCM has received publishing royalties from a publication relating to health care.
Ruchira M. Jha, MD (Barrow Neurological Institute)	Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. An immediate family member of Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Legal fees. The institution of Dr. Jha has received research support from NIH/NINDS, Chuck Noll Foundation, University of Pittsburgh, Barrow Neurological Foundation.
Dhivyaa Rajasundaram (University of Pittsburgh)	Dhivyaa Rajasundaram has nothing to disclose.

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