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Regulation of Pain by Bacterial Proteases and Protease-activated Receptors

Award Number: R01DK145946
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Regulation of Pain by Bacterial Proteases and Protease-activated Receptors - Painful gastrointestinal diseases are associated with an imbalance of bacteria (dysbiosis) and activation of protease-activated receptor 2 (PAR2) on colonic nociceptors. However, the identity and mechanism of action of bacterial proteases that activate PAR2 and lead to sustained neuronal signaling to produce chronic visceral pain are unknown. The long-term goal is to provide new information about the mechanisms of bacterial protease- evoked colonic pain and validate targeted PAR2 antagonists for treatment of pain generated by colonic dysbiosis. The overall objectives are to (i) identify proteases secreted by colonic bacteria that cleave and activate PAR2 on nociceptors to cause colonic pain; (ii) elucidate the signaling pathways by which bacterial proteases and PAR2 sensitize nociceptors; and (iii) validate PAR2 as a therapeutic target for bacterial protease-evoked colonic pain. The central hypothesis is that bacteria in the colon secrete proteases that cleave PAR2 on nociceptor terminals in the gut wall, and differential cleavage of PAR2 by the different proteases leads to sustained intracellular signaling, which can be targeted with nanoparticles (NPs) loaded with PAR2 antagonists for the treatment of visceral pain. The rationale for this project is that identification of bacterial proteases and host PAR2 that signal colonic pain will provide insights into the mechanisms of poorly understood forms of visceral pain and will identify PAR2 as a therapeutic target for dysbiosis-associated visceral pain. The central hypothesis will be tested by pursuing three specific aims: 1) Identify proteases secreted by human colonic bacteria that cause PAR2- dependent colonic nociception; 2) Determine the mechanisms by which bacterial proteases and PAR2 signal from subcellular compartments to sensitize nociceptors and produce nociception; and 3) Develop antagonists of PAR2 signaling in subcellular compartments for treatment of bacterial protease-evoked colonic nociception. Under the first aim, bacterial proteases with highest activity for cleaving PAR2 will be identified using covalent inhibitors and chemical proteomics. For the second aim genetically-encoded bioluminescence resonance transfer (BRET) and Förster resonance energy transfer (FRET) biosensors will be used to analyze PAR2 signaling in nanodomains of nociceptors with high spatial and temporal fidelity. In the final aim, NPs will be developed that preferentially deliver PAR2 antagonists to endosomes of colonic nociceptors for the treatment of colonic nociception. The proposed research is innovative because it investigates a clinically important yet unanswered question, which is the mechanism by which bacterial proteases activate PAR2 on the plasma membrane and within intracellular compartments of colonic nociceptors to produce chronic pain. The proposal is significant because it will generate new information about the mechanisms of bacterial protease-evoked colonic pain and will validate targeted PAR2 antagonists loaded into NPs for analgesic relief. The resulting knowledge holds the potential to provide new opportunities for the treatment of colonic pain and the associated gastrointestinal disorders.


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: 2026 ( Subtotal = $3,853,465 )
2026	2026	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/7/2026	NEW	$3,853,465
2026	2026	NEW YORK UNIVERSITY	70 WASHINGTON SQ S FL 11	NEW YORK	NY	10012	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/9/2026	NEW	$0
														Subtotal = $3,853,465

Grand Total All Awards = $3,853,465

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Regulation of Pain by Bacterial Proteases and Protease-activated Receptors

Award Number: R01DK145946

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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