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Genetic and Molecular Mechanisms of PGE2-EP4-Induced Goblet Cell Metaplasia in Asthma

Award Number: R01HL185359
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Genetic and Molecular Mechanisms of PGE2-EP4-Induced Goblet Cell Metaplasia in Asthma - PROJECT SUMMARY Asthma affects 25 million Americans and is characterized by airway inflammation, goblet cell hyperplasia, and mucus plugging, which contribute to airflow obstruction and symptoms. While type 2 targeted therapies reduce symptoms in some patients, many patients exhibit residual disease or lack therapeutic options due to non-T2 inflammatory pathways. We discovered that PGE2, which is elevated in both T2-high and T2-low asthma, promotes goblet cell hyperplasia through EP4 receptor activation. We also found that genetic polymorphisms in PTGER4 (encoding EP4) regulate receptor expression in airway epithelium and are associated with asthma risk. This proposal aims to: 1) determine the EP4-mediated signaling pathways leading to goblet cell hyperplasia using primary human airway epithelial cells cultured at air-liquid interface, focusing on the CREB signaling pathway; 2) establish the relationship between airway PGE2 metabolites, epithelial activation, and clinical outcomes in severe asthma using the SARP3 cohort; and 3) investigate how EP4 expression is regulated in the airway epithelium in health and disease. Our approach combines biophysical, cellular, molecular, and genetic analyses with clinical phenotyping. We will use chemical inhibitors to target specific signaling pathways, assess mucus gel rheology with magnetic microwire rheometry, and analyze gene expression in airway epithelial cells by genotype. The SARP3 cohort provides extensive clinical phenotyping, including CT mucus scores and longitudinal outcomes. This work will identify novel therapeutic targets for mucus dysfunction in both T2-high and T2-low asthma and define patient populations most likely to benefit from pathway-specific interventions based on clinical and genetic features.


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 = $3,205,321 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	1	8/19/2026	NEW	$3,205,321
														Subtotal = $3,205,321

Grand Total All Awards = $3,205,321

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Genetic and Molecular Mechanisms of PGE2-EP4-Induced Goblet Cell Metaplasia in Asthma

Award Number: R01HL185359

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/20/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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