# Role of a novel human mast cell G protein coupled receptor in Allergy and Inflammation

> **NIH AI R01** · UNIVERSITY OF PENNSYLVANIA · 2026 · $487,300

## Abstract

Summary:
 Mast cells (MCs) are best known for their roles in IgE-mediated allergic disorders. However, the recent
identification of Mas-related G protein coupled receptor-X2 (MRGPRX2) in human cutaneous MCs (MrgprB2;
mouse counterpart) as the receptor for antimicrobial peptides, neuropeptides and chemokines has revolutionized
the way in which MCs are viewed. Furthermore, the development of MrgprB2-/- mice has been instrumental in
delineating the roles of this receptor in non-IgE-mediated disorders. However, it now appears that expression of
MrgprB2 is not restricted to cutaneous MCs and that it is also present in lung and gut MCs. We made the
surprising observation that in addition to cutaneous disorders MrgprB2 contributes to allergic lung inflammation.
 MrgprB2 displays only ~62% sequence similarity with human MRGPRX2 and specific inhibitors of the
human receptor do not block responses to the mouse receptor. Therefore, studies conducted with mice
expressing MrgprB2 may not fully represent disease conditions in humans. To overcome this major hurdle, we
utilized CRISPR/Cas9-mediated gene targeting strategy and MC knock-in procedure to replace the endogenous
mouse MrgprB2 with functional human MRGPRX2. In aim 1, we will delineate the role of MRGPRX2 on
experimental psoriasis and allergic asthma and test the ability of specific inhibitors to modulate these responses.
We will delineate how gain- and loss-of-functional variants of MRGPRX2 modulate MC signaling in vitro and
disease phenotype in vivo. We will perform spatial transcriptomic analysis to delineate how pharmacologic and
genetic modulation of the receptor regulate signaling in MCs and their neighboring immune and non-immune
cells in the context of psoriasis and allergic asthma. We found that β-arrestin1, but not β-arrestin2, promotes
MRGPRX2 internalization in response to substance P in human skin MCs. By contrast, β-arrestin2 contributes
to MrgprB2-mediated NF-κB/ERK phosphorylation and cytokine generation in

## Key facts

- **NIH application ID:** 11376336
- **Project number:** 2R01AI124182-06A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Hydar  Ali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $487,300
- **Award type:** 2
- **Project period:** 2016-09-23T00:00:00 → 2031-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11376336

## Citation

> US National Institutes of Health, RePORTER application 11376336, Role of a novel human mast cell G protein coupled receptor in Allergy and Inflammation (2R01AI124182-06A1). Retrieved via AI Analytics 2026-07-21 from https://api.ai-analytics.org/grant/nih/11376336. Licensed CC0.

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