# ECM Regulation of Ocular Surface Disease

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $442,500

## Abstract

ABSTRACT
 Bacterial keratitis is a serious public health threat associated with significant ocular morbidity and is one of
the major causes of blindness worldwide. By one estimate, the annual incidence of bacterial keratitis is
approximately 500,000 patients worldwide. Even with modern day treatment, corneal infections can result in
poor vision in 50% and surgical intervention in 12% of patients. Several Gram-positive and Gram-negative
bacterial pathogens can infect the cornea and cause keratitis. Bacterial pathogens use all resources available
to survive in the hostile host environment. Subversion of host extracellular matrix (ECM) components and their
receptors as attachment sites is thought to be a common virulence mechanism shared by many bacteria.
However, there are few data that clearly support this idea in vivo. We found in preliminary studies that deletion
of syndecan-1 (Sdc1), a major cell surface heparan sulfate proteoglycan (HSPG) of epithelial cells, causes a
gain of function in a mouse model of scarified corneal infection, where Sdc1-/- corneas are significantly less
susceptible to Streptococcus pneumoniae infection. Topical administration of excess Sdc1 ectodomains or
heparan sulfate (HS) significantly inhibits S. pneumoniae corneal infection, suggesting that HS chains of Sdc1
promote infection as a cell surface attachment receptor. However, S. pneumoniae does not interact with Sdc1
and Sdc1 is shed upon S. pneumoniae infection, indicating that Sdc1 does not directly support S. pneumoniae
adhesion. Instead, Sdc1 promotes S. pneumoniae adhesion by driving the assembly of fibronectin (FN) fibrils
in the corneal basement membrane to which S. pneumoniae attaches when infecting injured corneas. Excess
Sdc1 ectodomains inhibit S. pneumoniae corneal infection by binding to the heparin-binding domain in FN, and
interfering with S. pneumoniae binding to FN. Based on these data, this proposal will examine the overall
hypothesis that specific ECM interactions coordinate the assembly of corneal basement membranes, and that
certain bacterial pathogens of the ocular surface exploit these normal biological processes to promote their
pathogenesis. This hypothesis will be tested in 3 Specific Aims. Aim 1 will define the structural basis of how HS
inhibits bacterial corneal infection. Aim 2 will determine the significance and relevance of bacteria-induced
Sdc1 shedding in corneal infection, and Aim 3 will elucidate the underlying mechanisms of how Sdc1 regulates
FN fibrillogenesis in the corneal basement membrane. These studies are expected to uncover previously
unknown functions of the ECM in the cornea and to establish a new integrated virulence pathway in bacterial
keratitis.

## Key facts

- **NIH application ID:** 10445477
- **Project number:** 1R01EY033025-01A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Pyong Woo Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,500
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445477

## Citation

> US National Institutes of Health, RePORTER application 10445477, ECM Regulation of Ocular Surface Disease (1R01EY033025-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10445477. Licensed CC0.

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