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Consequences of mast cell activation and complement dysregulation in eosinophilic esophagitis

Award Number: K08AI187712
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/13/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Consequences of mast cell activation and complement dysregulation in eosinophilic esophagitis - PROJECT SUMMARY Eosinophilic esophagitis (EoE) is a chronic, food-induced allergic inflammatory disease that has an increasing prevalence, estimated to affect 450,000 individuals in the USA with a healthcare burden of 1.4 billion dollars/year. It is now recognized as the most common reason for chronic dysphagia in young adults. EoE histopathology involves epithelial alterations, including hyperplasia and decreased barrier integrity, as well as lamina propria fibrosis. Despite eosinophils being pathognomonic to EoE diagnosis, recent clinical trials with eosinophil- depleting antibodies showed that eosinophils are not the primary causal cell. Mast cells (MC) associate more closely than eosinophils with important disease symptoms and histologic and endoscopic changes, are significantly increased in EoE, and produce IL-13, an essential driver of EoE. A novel machine learning protocol that we developed (MC-AI) showed significant MC activation in EoE epithelium and lamina propria. However, the mechanisms of MC activation and contribution to disease pathology, including epithelial dysfunction and fibrosis, are unclear. These data highlight a potential clinical need for MC-targeted EoE therapies and the related search for mechanisms of MC activation. Our preliminary data show that the gene encoding the receptor for the anaphylatoxin/ MC activator C3a, C3AR1, is overexpressed in the esophagus of patients with EoE. C3AR1 expression correlates strongly with expression of MC-specific genes and is enriched in MCs by single-cell RNA sequencing (scRNAseq). Additionally, C3aR protein levels on MCs are proportional to esophageal MC levels and activation status. C3a is generated when complement component 3 (C3) protein is cleaved into the bioactive fragments C3a and C3b. Esophageal C3a is increased in patients with EoE compared to control subjects and present in the epithelium and lamina propria, the locations where we and others have identified MCs in EoE. In the lamina propria, fibroblasts are key producers of C3, and C3 expression is increased in fibroblasts in patients with EoE compared to control individuals. Notably, C3 is the most upregulated esophageal gene in an animal model of EoE compared to controls. These and the additional observations described below give rise to our central hypothesis that mediators released by C3a-activated mast cells (MCs) contribute to epithelial dysfunction and fibrosis in eosinophilic esophagitis (EoE). We will test this hypothesis through a combination of in vitro and in vivo models. To achieve this, I will learn skills in murine models, RNA sequencing/bioinformatics, statistics, and advanced flow cytometry. Completion of these research and career development goals will successfully transition me into an independent physician-scientist with a translational laboratory that combines clinical and basic laboratory research to study the role of mast cells in EGID, with an initial focus on EoE.


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 = $207,995 )
2026	2026	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Allergy and Infectious Diseases Research	000	1	4/13/2026	NEW	$207,995
														Subtotal = $207,995

Grand Total All Awards = $207,995

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Consequences of mast cell activation and complement dysregulation in eosinophilic esophagitis

Award Number: K08AI187712

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/13/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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