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

Award Number: R01AI185203
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $357,500 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	000	2	4/14/2025	NON-COMPETING CONTINUATION	$357,500
														Subtotal = $357,500

Issue Date FY: 2024 ( Subtotal = $357,500 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	001	1	9/4/2024	NEW	$35,750
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Allergy and Infectious Diseases Research	000	1	5/15/2024	NEW	$321,750
														Subtotal = $357,500

Grand Total All Awards = $715,000

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

Award Number: R01AI185203

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/15/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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