# Targeting chondroitin sulfate proteoglycan 4 (CSPG4) expression as a Clostridioides difficile therapeutic

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $357,500

## Abstract

Binding to host receptors is a fundamental step in the mechanisms of action for many bacterial
toxins, particularly toxins produced by Clostridioides difficile. Blocking or otherwise abrogating
toxin binding to receptors not only protects against cytotoxicity but can also in many cases totally
prevents disease. In this work, we are investigating a new approach for preventing toxins from
engaging cell surface receptors by targeting host signaling pathways that regulate the expression
of toxin receptors. Targeting signaling pathways is central to the design of various cancer
therapeutics but has not been as readily explored as a treatment strategy for bacterial pathogens.
In these studies, we are pursuing this idea by identifying and investigating a host signaling
pathway that regulates the C. difficile toxin receptor chondroitin sulfate proteoglycan 4 (CSPG4).
As a key receptor for C. difficile toxins, CSPG4 is required for the manifestation of C. difficile
disease and eliminating the expression prevents C. difficile disease. In our preliminary work,
signaling networks regulating the expression of CSPG4 were identified utilizing a toxin-resistance
system that discovered the Hippo pathway controls the expression of CSPG4. Our preliminary
studies have demonstrated small molecule inhibitors of Hippo signaling down regulate CSPG4 in
vitro and in vivo. Importantly, we were able to protect mice from C. difficile disease by inhibiting
Hippo signaling during the primary phase of disease. Building directly from our initial work, Aim
1 will further explore the underlying mechanisms utilized by Hippo signaling to regulate CSPG4
in the presence of C. difficile toxins. Aim 2 will provide fundamental information about how CSPG4
expression patterns in the colon are connected to C. difficile pathogenesis. Aim 3 will assess the
therapeutic effectiveness of targeting the Hippo-CSPG4 axis during various clinical
manifestations of C. difficile disease. Collectively, these proposed studies will address a critical
unmet need by targeting the Hippo-CSPG4 axis as a treatment for C. difficile and by advancing
the paradigm of developing therapeutics based on signaling pathways regulating toxin receptors.

## Key facts

- **NIH application ID:** 10944984
- **Project number:** 1R01AI185203-01
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Jason Larabee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $357,500
- **Award type:** 1
- **Project period:** 2024-05-15 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944984

## Citation

> US National Institutes of Health, RePORTER application 10944984, Targeting chondroitin sulfate proteoglycan 4 (CSPG4) expression as a Clostridioides difficile therapeutic (1R01AI185203-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10944984. Licensed CC0.

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