# PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2023 · $463,382

## Abstract

Project Summary, UC San Diego, Project 3
The aims of Project 3 address the central hypothesis of the overall program: Protein glycosylation and
glycoprotein remodeling alter the coagulopathy and inflammation of sepsis. Project 3 will investigate remodeling
of the vascular glycocalyx induced by sepsis and how these changes affect host response and survival in mice.
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, proteomics
and glycobiology. From recent literature and preliminary data, it is well known that sepsis induces changes in
the composition of plasma glycoproteins and shedding of the vascular endothelial glycocalyx, leading to vascular
dysfunction and high mortality. However, little information is available about the composition of the vascular
proteome and glycoproteome and how it changes in response to different infectious agents. Over the last grant
cycle, we developed an in vivo tagging method that allows assessment of the vascular proteome in different
organs. We showed that infection by methicillin-resistant Staphylococcus aureus (MR) results in remodeling of
the vascular proteome in an organ-specific manner, leading to the discovery of proteoglycan 4 and factors that
modulate hyaluronan metabolism as potential novel markers of infection. We also showed that heparan sulfate
produced by the vascular endothelium plays an important role in determining the severity and outcome of sepsis
in mice. In the liver, undersulfation of endothelial heparan sulfate protects against the inflammatory response
and coagulopathy induced by MR. However, in the heart, pathological changes take place that correlate with
hypersensitivity to Staphylococcus aureus alpha-hemolysin, a key virulence factor. In the next cycle, we will
expand the in vivo tagging method to include other common bacterial pathogens that cause sepsis in humans in
order to identify operative pathogenic mechanisms and to determine if sepsis can be stratified by responses in
the vascular wall to different pathogens. We will examine the mechanism by which heparan sulfate modulates
alpha-hemolysin sensitivity. We will determine if the induction of proteoglycan 4 and hyaluronan metabolism are
general hallmarks of sepsis and if these factors serve a protective role. We also showed that proteoglycan 4 and
hyaluronan accumulate in human plasma samples from patients with sepsis. We will correlate these markers
with clinical information about the patients to determine if these markers stratify sepsis and whether they have
value as diagnostic or prognostic markers. The overarching goal is to understand if infection-induced remodeling
of the vascular glycoproteome provides a window to identify disease mechanisms and a way to stratify sepsis
across time, different infectious agents, and during disease resolution.

## Key facts

- **NIH application ID:** 10641853
- **Project number:** 5P01HL131474-08
- **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:** 2023
- **Award amount:** $463,382
- **Award type:** 5
- **Project period:** 2016-07-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10641853

## Citation

> US National Institutes of Health, RePORTER application 10641853, PROJECT 3 - Infection-Induced Remodeling of the Vascular Proteome (5P01HL131474-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10641853. Licensed CC0.

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