# Proteoglycan-Chemokine Interactions in Lung Disease

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $485,256

## Abstract

The major goal of this R01 proposal is to understand how heparan sulfate proteoglycans (HSPGs)
regulate the formation of chemokine gradients, recruitment of inflammatory cells, and bacterial killing
mechanisms in bacterial pneumonia. Leukocyte trafficking is a highly selective, nonrandom process and
chemokines play a major role in guiding the directional migration of leukocytes from the bloodstream to the site
of inflammation. Chemokine gradients are thought to form because chemokines move away from the source of
production by diffusion and get tethered to cell surface and matrix HSPGs on the way. While quite a bit is
known about the heparan sulfate (HS) binding epitopes on chemokines, less is known about the structural
features of HS that enable HSPGs to bind and regulate chemokines. Moreover, HSPGs are biologically active
molecules, expressed in distinct spatiotemporal patterns in tissues, and HSPGs themselves are highly
regulated during an inflammatory response, but how these mechanisms impact HSPG-chemokine interactions
in vivo are largely unknown. Furthermore, recent studies suggest that certain bacteria subvert HSPGs to inhibit
host defense. Preliminary studies showed that early neutrophil recruitment to the lung is increased in
syndecan-1 null (Sdc1-/-) mice infected with Staphylococcus aureus compared to wild type (Wt) mice, which
led to increased clearance and significantly decreased bacterial burden in Sdc1-/- lungs. The basis of these
gain of function phenotypes was traced to an increased binding of chemokines by cell surface HSPGs of type II
epithelial (AT2) cells and increased steepness of the immobilized chemokine gradient from the endothelium to
the alveolar epithelium in infected Sdc1-/- lungs. Based on these data, we hypothesize that: i) certain structural
features of HSPGs expressed in different lung compartments differentially regulate the formation and activity of
chemokine gradients; ii) syndecan-1 inhibits the formation of immobilized haptotactic chemokine gradients; and
that iii) S. aureus subverts syndecan-1 to inhibit the formation and activity of chemokine gradients and to inhibit
innate immune defense mechanisms. These hypotheses will be tested in 3 specific aims. Aim 1 will determine
the structural features of how HSPGs regulate chemokines in bacterial pneumonia. Aim 2 will define how
syndecan-1 inhibits chemokine gradients and neutrophil recruitment in bacterial pneumonia. Aim 3 will
determine the underlying mechanisms of how syndecan-1 inhibits neutrophil-mediated defense mechanisms in
bacterial pneumonia. These studies are expected to significantly refine the current chemokine gradient concept
and to reveal new mechanisms of how bacteria subvert HSPGs for their pathogenesis in the lung.

## Key facts

- **NIH application ID:** 9881190
- **Project number:** 5R01HL132573-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Pyong Woo Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,256
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881190

## Citation

> US National Institutes of Health, RePORTER application 9881190, Proteoglycan-Chemokine Interactions in Lung Disease (5R01HL132573-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9881190. Licensed CC0.

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