# Vascular Barrier Leakage in Inflammation

> **NIH NIH R35** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $893,838

## Abstract

PROJECT SUMMARY/ABSTRACT
Vascular barrier dysfunction causes aberrant transport of blood components into the vessel wall or surrounding
tissues, a hallmark of inflammatory injury in response to trauma, sepsis, atherosclerosis, diabetes, and stroke.
Currently, there are no effective therapies that directly target the leaky barrier, as drug development has been
hampered by knowledge gaps and difficulties in translating cell/animal data to human pathophysiology. Our
program addresses these challenges via comparative analyses of endothelial barrier structure and function in
human and animal models of inflammatory injury. We conduct three series of studies in the blood, blood-vessel
interface and endothelial barrier structure, aimed at 1) identifying key circulating factors that cause barrier
leakage and their cell-specific mechanisms of production and action; 2) characterizing endothelial surface
receptors and intracellular signals that transduce their effects; and 3) elucidating molecular events in cell-cell
junctions, cytoskeleton, and glycocalyx that ultimately lead to barrier opening. Our work has continuously been
supported by the NHLBI contributing to the development of novel techniques and transformative theories in
vascular permeability. We were among the first to characterize the nmMLCK signaling in endothelial junction
dynamics and paracellular permeability during leukocyte activation. Recently, we reported the discovery of a
new post-translational modification pathway, dhhc21-mediated protein palmitoylation, in microvascular leakage
and leukocyte-endothelium interactions following infection and sterile injury. Built on these exciting findings, our
program continues to advance by exploring novel diagnostic/therapeutic targets with mechanistic insights that
will transform the paradigm of inflammation. Current efforts are directed to the characterization of neutrophil
extracellular traps, histones and microvesicles, focusing on their cell-specific mechanisms of generation and
function in the microcirculation. Studies are on-going to test the roles of palmitoylation in vesicle biogenesis,
cargo composition and interaction with endothelial cells. The barrier-disrupting effects of these factors will be
uncovered with in-depth molecular details on endothelial glycocalyx receptors, intracellular signal transduction,
and post-translational modification (palmitoylation) of junction structures. We use a multifaceted approach that
incorporates innovative molecular biology and imaging techniques (many developed in our lab) into functional
analyses of vascular permeability under clinically relevant conditions. Complementary in vitro, ex vivo, and in
vivo experiments are designed testing pharmacological activators and inhibitors, molecular manipulations, and
genetic/chimeric alterations at cell-tissue-body levels. A unique aspect of our program lies in the translational
impact achieved through the studies with intact functionally viable human organs.

## Key facts

- **NIH application ID:** 9892082
- **Project number:** 1R35HL150732-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Sarah Y Yuan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $893,838
- **Award type:** 1
- **Project period:** 2020-05-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892082

## Citation

> US National Institutes of Health, RePORTER application 9892082, Vascular Barrier Leakage in Inflammation (1R35HL150732-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9892082. Licensed CC0.

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