# Syndecan Regulation of Sepsis Host Defense

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $501,434

## Abstract

Sepsis is a serious infectious inflammatory syndrome that develops when the initial host response fails to
contain the infection. The mortality associated with sepsis remains unacceptably high and is still over 25%
among approximately 750,000 patients annually in the US alone. Worldwide, the yearly incidence of sepsis
and severe sepsis is estimated at an astounding 31 million and 24 million cases. Many mediators of sepsis
have been identified, and many clinical trials have tested the efficacy of targeting these molecules and their
mechanisms, but with one short-lived exception, none of these has resulted in an effective and specific
treatment for sepsis. These data clearly indicate an unmet need for therapeutic options in sepsis and suggest
that new targets, pathways and ideas need to be examined and existing paradigms need to be refined.
Neutrophils are a fundamental component of the innate immune response and essential for microbial
containment and eradication for sepsis survival. Downregulation of the innate immune response has been
described to have adverse outcomes in preclinical and clinical sepsis. However, molecular mechanisms that
suppress and dysregulate innate host responses have yet to be clearly defined, and this gap in knowledge
represents one of the major barriers to therapeutic advances in the field. Our preliminary studies suggest that
syndecan-1, a major cell surface heparan sulfate proteoglycan (HSPG), promotes severe infections in sepsis
by inhibiting neutrophil recruitment to sites of infection and by inhibiting extracellular killing mechanisms of
neutrophils in a heparan sulfate (HS)-dependent manner. Unlike other means of neutrophil suppression,
syndecan-1 alters the efficacy of neutrophil migration prior to the onset of its journey to infection sites. This
proposal will examine the hypothesis that syndecan-1 is a critical factor that regulates innate immune
suppression in sepsis in 3 specific aims. Aim 1 will define the structural features that enable syndecan-1 HS to
promote sepsis. Aim 2 will explore the biological mechanisms of how syndecan-1 suppresses innate immune
responses in sepsis. Aim 3 will elucidate the septic pathways that lead to the shedding of syndecan-1
ectodomains and determine the significance of this mechanism in the progression of sepsis. Through these
studies, the culminating goal of this proposal is to uncover previously unknown fundamental functions of
syndecan-1 in sepsis and to increase our understanding of molecular and cellular pathways that are central to
innate immune suppression in sepsis.

## Key facts

- **NIH application ID:** 10191013
- **Project number:** 5R01HL142213-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Pyong Woo Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $501,434
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191013

## Citation

> US National Institutes of Health, RePORTER application 10191013, Syndecan Regulation of Sepsis Host Defense (5R01HL142213-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10191013. Licensed CC0.

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