# Project 3: Heparan Sulfate Proteoglycans in the Pathogenesis of Sepsis

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $532,405

## Abstract

SUMMARY
The aims of this project address the central hypothesis of the overall program, that Protein glycosylation and
glycoprotein remodeling modulate the coagulopathy and inflammation of sepsis. This research project will
investigate the roles of heparan sulfate (HS), heparan sulfate proteoglycans (HSPGs), and matrix
metalloproteases (MMPs) in the coagulopathy and inflammation of sepsis. The proposed research engages all
of the core facilities of the program and draws on the combined expertise of the Project Leaders and Core
Leaders in infection and sepsis, inflammatory biology, coagulation, coagulopathy, proteomics, and glycobiology.
From recent literature and preliminary data, HS attached to endothelial HSPGs alters the outcome of sepsis
coincident with HSPG shedding from vascular endothelial cells induced by MMPs. Moreover, vascular HS
deficiency has opposing effects on the outcomes of sepsis caused by different microbial pathogens including
Gram-positive Streptococcus pneumoniae (SPN) and Gram-negative Salmonella enterica Typhimurium (ST).
In addition, MMP inhibition affects HSPG shedding and provides a protective role in the pathogenesis of sepsis
caused by ST. These findings infer the possibility that the pathogenesis of sepsis may be stratified by different
host responses in the context of distinct pathogens. Research proposed in Project 3 will further test the
hypothesis that the major HSPGs expressed on the vascular endothelium, namely syndecan-1, syndecan-2,
syndecan-4, and glypican-1, compose a functional nexus with MMPs that confer separate outcomes in the
coagulopathy and inflammation of sepsis caused by these bacterial pathogens and Gram-negative Escherichia
coli (EC). This project will also generate unique knowledge about the repertoire of HSPG-protein complexes in
disease onset and progression. The proposed studies will focus on HSPGs and HS-binding proteins in mice
and humans during sepsis caused by Gram-negative and Gram-positive pathogens, and in Systemic
Inflammatory Response Syndrome (SIRS) and may yield new potential biomarkers and novel approaches to
modulating the outcomes of sepsis and SIRS. The interdisciplinary expertise of the Project Leaders and Core
Leaders, and the combined resources available, will achieve a mechanistic understanding of HSPG
homeostasis and HSPG-protein complex determinants implicated in modulating the coagulation, coagulopathy,
inflammation, and outcomes of SIRS and sepsis due to infections involving different pathogens.

## Key facts

- **NIH application ID:** 9916816
- **Project number:** 5P01HL131474-05
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Jeffrey D Esko
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $532,405
- **Award type:** 5
- **Project period:** — → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916816

## Citation

> US National Institutes of Health, RePORTER application 9916816, Project 3: Heparan Sulfate Proteoglycans in the Pathogenesis of Sepsis (5P01HL131474-05). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9916816. Licensed CC0.

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