# Roles of novel MRGPRX2/MrgprB2 signaling in mast cells on host defense and Inflammation

> **NIH AI R01** · UNIVERSITY OF PENNSYLVANIA · 2026 · $1,909,388

## Abstract

Summary:
Mast cells (MCs) are tissue-resident immune cells that are best known for mediating IgE/FcεRI-mediated
hypersensitivity and atopic disorders. However, recent excitement in MC research has been the realization that
a diverse group of cationic amphipathic peptides and FDA-approved drugs activate human MCs via a novel G
protein coupled receptor (GPCR) known as MRGPRX2 (mouse counterpart, MrgprB2). This receptor is
implicated in host defense, immediate drug hypersensitivity reactions (IDHRs), neurogenic inflammation/pain
and a variety of cutaneous disorders. Not surprisingly, there is an intense interest in developing MRGPRX2
inhibitors for treating MC-mediated disorders. Although several small molecule inhibitors have been developed,
a phase 2 clinical trial with a promising lead was recently paused because of toxicity issues, emphasizing the
need for additional approach. This proposal is focused on two sets of proteins that directly interact with GPCRs
(G proteins and GPCR kinase 2, GRK2) that are traditionally viewed as displaying opposing effects on receptor
function. We will test the novel hypothesis that G proteins and GRK2 interact with MRGPRX2 to promote
MC-mediated IDHRs, anaphylaxis and cutaneous disorders.
In aim 1, we will knockdown the expression of Gαi and Gαq family of G proteins in human MCs and determine the
impact of this deletion on MRGPRX2-mediated responses in vitro. We will use retrovirus to express MRGPRX2
in marrow-derived MCs (BMMCs) in the absence of G proteins. These BMMCs will be engrafted into MC-deficient
mice. This approach will be used to determine the role of specific G proteins on MRGPRX2-mediated IDHRs,
anaphylaxis, rosacea and psoriasis in vivo. We will express MRGPRX2 variants with defective coupling to
different G proteins in BMMCs and these cells will be engrafted into MC-deficient to mice. This strategy will be
used to determine the impact of disrupting MRGPRX2/G protein interaction on disease phenotype in vivo. In aim
2,

## Key facts

- **NIH application ID:** 11305722
- **Project number:** 2R01AI149487-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Hydar  Ali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $1,909,388
- **Award type:** 2
- **Project period:** 2019-12-01T00:00:00 → 2030-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11305722

## Citation

> US National Institutes of Health, RePORTER application 11305722, Roles of novel MRGPRX2/MrgprB2 signaling in mast cells on host defense and Inflammation (2R01AI149487-06). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/11305722. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*