# Alterations to endothelial membrane composition and structure as a driver of the endotheliopathy of trauma

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2024 · $328,950

## Abstract

Project Abstract
Severe hemorrhage is a life-threatening condition that often occurs in trauma. Hemorrhagic shock and the
hypotension and tissue ischemia that results is associated with endothelial damage and dysfunction that is
thought to contribute to associated complications and death. Recently, it has been appreciated that a
proteoglycan structure that lines blood vessels, known as the endothelial glycocalyx, is damaged during
trauma and hemorrhage. This glycocalyx damage is thought to contribute to generalized blood vessel
disfunction, multi-organ failure, and coagulopathy, together termed the Endotheliopathy of Trauma. Trauma
patients with high plasma glycocalyx components die at higher rates, both due to uncontrolled hemorrhage, as
well as an increase in multi-organ failure. Despite the potential importance of this mechanism, signaling events
leading to acute endothelial glycocalyx shedding are largely undefined. We have previously found that
metabolism of the citric acid cycle intermediate succinate drives the acute shedding of the glycocalyx. We also
observed an increase in membrane lysophospholipids in a cell culture model of hypoxia-reoxygenation, as well
as increases in the interaction between matrix metalloproteinases (MMPs) and the glycocalyx constituent
syndecan-1. These findings led us to hypothesize that the increased succinate metabolism during hemorrhage-
resuscitation causes reactive oxygen species production and lipid oxidation, which leads to phospholipase A2-
mediated generation of lysophospholipids and plasma membrane reorganization, allowing MMPs to degrade
the glycocalyx. We propose that a specialized protein-lipid domain forms in the plasma membrane consisting
of lysophospholipids, MMPs, and glycocalyx proteins, which we term a “sheddosome” domain. In two specific
aims, we will 1.) Determine how membrane reorganization mediates glycocalyx shedding through the formation
of “sheddosome” domains in a general hypoxia-reoxygenation model. 2.) Determine how lysophospholipid-
mediated membrane reorganization leads to the endotheliopathy of trauma. This work will define a mechanism
by which alterations in succinate metabolism drive changes in membrane structure, leading to glycocalyx
damage, coagulopathy, and organ failure. This new knowledge of the acute vascular events in traumatic
hemorrhage will inform future therapies to increase survival in these patients.

## Key facts

- **NIH application ID:** 10882205
- **Project number:** 1R01GM151631-01A1
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Olan Jackson-Weaver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $328,950
- **Award type:** 1
- **Project period:** 2024-07-10 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882205

## Citation

> US National Institutes of Health, RePORTER application 10882205, Alterations to endothelial membrane composition and structure as a driver of the endotheliopathy of trauma (1R01GM151631-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10882205. Licensed CC0.

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