National Institute of Allergy and Infectious Diseases 1R21AI190597-01A1

Mast Cell G-protein Coupled Receptors in Immune Modulation of colitis

This award funds research on the role of Mast Cell G-protein Coupled Receptors, specifically MRGPRX2, in the immune modulation of ulcerative colitis. The study investigates genetic variations affecting receptor function and their impact on disease outcomes using mouse models.

Description

Ulcerative colitis is a subtype of inflammatory bowel disease with symptoms of abdominal pain and bloody diarrhea secondary to colonic inflammation. Human colonic mast cells (MCs) express a novel G protein-coupled receptor known as Mas-related GPCR-X2 (MRGPRX2, mouse ortholog, MrgprB2), and RNAseq analysis of inflamed UC samples demonstrated enhanced expression of MRGPRX2 agonists and MC proteases when compared to non-inflamed samples. It is well documented that GPCRs undergo desensitization following their phosphorylation at Ser/Thr residues. Interestingly, analyses of human GPCR protein-altering single nucleotide polymorphism (SNP) from exome chip data of inflammatory bowel disease showed that N62S (rs10833049) mutation of MRGPRX2, which results in the creation of a phosphorylation site, is associated with a protective phenotype in UC. Conversely, the S325L SNP results in reduced desensitization and greater degranulation than the WT receptor. The study aims to utilize MRGPRX2-KI, WT, and MrgprB2-/- mice to test the hypothesis that MRGPRX2 in colonic MCs contributes to UC and that its phosphorylation and desensitization modulate disease outcome. The project will also explore how SNPs on MRGPRX2 influence experimental UC using retrovirus-mediated expression in mast cells. Successful completion will characterize a new preclinical model of UC and provide insights into how individual genetic variations in MRGPRX2 affect disease phenotype.

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