# Disintegrin Metalloprotease and Endothelial Dysfunction in Sepsis

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $284,050

## Abstract

PROJECT SUMMARY/ABSTRACT
Snakebite victims often present with sepsis-like symptoms, such as edema and respiratory distress syndrome.
Analyses of snake venoms have identified a family of proteases characteristic of disintegrin metalloproteases
(ADAMs) with the capability to cleave transmembrane molecules. Our previous work supported by this grant
has focused on a unique member of this family, ADAM15, with respect to its molecular structure and function in
regulating endothelial barrier property. We reported ADAM15 upregulation in the lungs and vascular tissues
during inflammation, where it increases endothelial permeability and promotes leukocyte migration via Src-
dependent signaling transduced by its cytoplasmic domain. In this renewal application, we plan to bring our
investigation on ADAM15 to the next level by examining its novel molecular targets with high translational
values and therapeutic potential. The studies will focus on endothelial glycocalyx, a barrier protective structure
composed of glycosaminoglycan chains linked to transmembrane proteoglycans and glycoproteins, which are
shed into the circulation following injury or major surgery. The central pathway to be tested is that during septic
injury, ADAM15 cleaves these transmembrane molecules leading to glycocalyx degradation. The exposure of
endothelium to circulating cells and agents, along with shedding products acting as hyperpermeability factors,
promotes plasma leakage and leukocyte diapedesis. Three specific aims are proposed: 1) to characterize
ADAM-induced glycocalyx injury during sepsis; 2) to elucidate the molecular mechanisms by which ADAM
causes glycocalyx degradation; and 3) to test the therapeutic potential of targeting the ADAM-glycocalyx
pathway for treating sepsis. We will employ complementary approaches that integrate physiological responses
and molecular reactions at organ, tissue, and cell levels. Innovative experimental models and therapies will be
tested. A unique design is the characterization of lung pathophysiology under clinically relevant conditions,
taking advantage of the available intact viable human organs provided by a federally certified organ
procurement organization. Data derived from the proposed work will provide new mechanistic insights into the
molecular pathogenesis of sepsis. The study will also assist in the identification and development of novel
therapeutic targets for treating vascular inflammatory injury associated with infection, trauma or major surgery.

## Key facts

- **NIH application ID:** 9908099
- **Project number:** 5R01GM097270-09
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Sarah Y Yuan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $284,050
- **Award type:** 5
- **Project period:** 2011-09-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908099

## Citation

> US National Institutes of Health, RePORTER application 9908099, Disintegrin Metalloprotease and Endothelial Dysfunction in Sepsis (5R01GM097270-09). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9908099. Licensed CC0.

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