[R21] Gain-of-function MRGPRX2 mutations in drug induced hypersensitivity reactions
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-06-30
Importo max: 243.750 EUR
Paese: US
Descrizione
Summary:
Mast cells (MCs) are best known for their roles in IgE-mediated allergic hypersensitivity reactions and
asthma. Immediate drug hypersensitivity reactions (IDHRs), including anaphylaxis, have increased significantly
worldwide in the last 25 years. However, the mechanism via which fluoroquinolone antibiotics, vancomycin and
neuromuscular blocking drugs cause IDHRs remained a mystery until the recent discovery that these drugs
activate MCs via a novel G protein coupled receptor (GPCR) known as Mas-related (GPCR)-X2 (MRGPRX2)
which is selectively expressed in MCs. However, IDHRs do not occur in all patients exposed to these drugs and
thus in vitro studies with MC degranulation does not predict hypersensitivity reactions in real life situations.
It has been proposed that gain-of-function single nucleotide polymorphisms (SNPs) or missense
mutations in MRGPRX2 contribute to IDHRs by enhancing receptor expression or activity. Recent studies with
human subjects indicated a correlation between the presence of two SNPs in MRGPRX2’s coding sequence
(N62S and S313R) with IDHRs to fluoroquinolones and vancomycin. However, it is not possible to isolate enough
MCs from patients for functional studies. Thus, critical barriers to progress in understanding how SNPs present
in MRGPRX2 contribute to modulation of MC function in vitro and IDHRs in vivo are the absence of appropriate
model systems. The goals of this exploratory R21 proposal are to develop and utilize novel mouse systems to
overcome these barriers. In specific Aim 1, we will use our newly developed humanized MRGPRX2 knock in
mouse model and CRISPR/Cas9 gene editing approach to generate mice expressing the two gain-of-function
SNPs (N62S and S313R). These mice will be utilized in Aim 2 to study for the first time impact of these SNPs
on receptor expression/function in vitro and IDHRs in vivo. Completion of this study may provide a new rationale
for the development of novel therapeutic approaches for modulating IDHRs.
Istituzione: UNIVERSITY OF PENNSYLVANIA
PI: Hydar Ali
Progetto: 1R21AI201990-01
Settori: National Institute of Allergy and Infectious Diseases
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.