Systemic Lipid Metabolism After Aneurysmal Subarachnoid Hemorrhage (SLIM-SAH)

PROJECT Aneurysmal annually occurs poor processes the translational changes incorporating injuries the dysfunction produce we develop preliminary developed outcomes increased membrane to related at collected mononuclear changes (scRNAseq) Aim metabolites produce SUMMARY/ABSTRACT Subarachnoid Hemorrhage (aSAH) is a type of hemorrhagic stroke that affects ~500,000 people worldwide and causes significant mortality and long-term disability. Delayed cerebral ischemia (DCI) between 4-21 days after aneurysm rupture in approximately 30% of aSAH patients and contributes to long-term outcomes. Despite considerable advances i n the understanding of the pathophysiological ontributing to DCI, treatments to prevent DCI have been ineffective. In this proposal, we investigate role of lipid metabolites in the development of DCI. Human biosamples will be utilized in order to assure relevance. We will 1) validate lipid biomarkers of DCI; 2) determine functional and gene expression in circulating, CSF, and skull bone marrow monocytes; and 3) develop machine learning (ML) models clinical, lipid, and gene expression data to improve prediction of outcomes after aSAH. Acute brain like aSAH result in substantial shifts in lipid metabolites. Increased CSF phospholipids are converted into proinflammatory lipid, lysophosphatidic acid (LPA), by the enzyme autotaxin (ATX). LPA results i n endothelial and contributes to the activation of inflammatory cells, including monocytes. ATX is also able to sphingosine-1-phosphate from sphingolipids. Using untargeted metabolomics aSAH plasma samples, have demonstrated that sphingosine and sphinganine are increased early among patients who went on to DCI. We developed targeted mass pectrometry-based assays to detect key lipid metabolites Our data have shown that both LPA and S1P are elevated in the CSF and plasma of patients who DCI. Incorporating these lipid metabolites into ML models improved the ability to predict DCI and after aSAH. Furthermore, using flow cytometry, we demonstrated that circulating monocytes are after aSAH and are shifted toward a non-classical phenotype characterized by mitochondrial hyperpolarization prior to the development of DCI. Treatment with an LPA r eceptor inhibitor was able reverse this hyperpolarization. Aim 1 will determine precise levels of targeted lipid metabolites (sphingosine- metabolites, LPAs, and lysophospholipids) from a cohort of aSAH admitted to the neurocritical care unit the University of Texas Health Science Center. These results will be validated in an independent, prospectively cohort from Johns Hopkins Hospital. Aim 2 will utilize prospectively collected peripheral blood cells (PBMCs), cerebral spinal fluid (CSF), and skull bone marrow derived cells to determine in monocyte function contributing to DCI. Both flow cytometry and single-cell RNA sequencing will be employed. Aim 3 will incorporate lipid metabolite data from Aim 1 and scRNAseq data from 3 into ML models for outcome prediction after aSAH. Completion of this proposal will validate l ipid playing a pathophysiological role after DCI and will identify therapeutic targets. Furthermore, we will clinically relevant models that can be used at bedside for prediction of outcomes. c s . Project Number: 1R01NS142408-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Aaron Gusdon | Institution: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON, HOUSTON, TX | Award Amount: $632,144 | Activity Code: R01 | Study Section: Brain Injury and Neurovascular Disorders Study Section[BIND] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298366