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NHERF1 regulates MRGPRX2/MrgprB2 responses in mast cells

Award Number: R01AI177305
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/12/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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NHERF1 regulates MRGPRX2/MrgprB2 responses in mast cells - PROJECT SUMMARY Mast cells are tissue resident innate immune cells that have been best characterized for their role in mediating allergic diseases. A new development in mast cell research has been the identification and characterization of a novel G-protein coupled receptor, Mas-Related G-Protein-coupled Receptor X2 (MRGPRX2). This receptor promotes pseudoallergic reaction to U.S. Food and Drug Administration (FDA)-approved drugs and chronic inflammation in diseases such as asthma, rosacea and hives (urticaria). While the role of MRGPRX2 in promoting allergic reactions has been thoroughly investigated, the molecular mechanisms utilized by this receptor is poorly understood. Our data suggests that Na+/H+ exchanger regulatory factor (NHERF)1, an adaptor protein, regulates MRGPRX2- and MrgprB2- (the mouse ortholog of the human receptor) induced responses in mast cells. Specifically, reducing the expression of NHERF1 in mast cells results in decreased intracellular Ca2+ mobilization and degranulation via MRGPRX2/MrgprB2 in vitro. Consistent with this data, NHERF1 also promoted anaphylaxis in MrgprB2-dependent mouse models of paw edema and passive systemic anaphylaxis in vivo. This proposal builds up on these observations; the central hypothesis is that NHERF1 is a critical regulator of MRGPRX2 responses in mast cells. Using a novel mouse strain that we have recently generated, Cpa3- Cre+:NHERF1fl/fl, primary human CD34+ stem cell-derived mast cells and humanized mice, we will determine the role of mast cell-specific expression of NHERF1 in regulating mouse MrgprB2 and human MRGPRX2 receptors in vitro and in vivo (Aim 1). In Aim 2, we will explore the mechanisms through which NHERF1 modulates mast cell response. Specifically, we will determine whether phosphorylation of NHERF1 is important for NHERF1 regulation of MRGPRX2/MrgprB2. We will identify the components of the NHERF1-interactome and signaling proteins and pathways through which NHERF1 functions in mast cells by using transcriptomic and proteomic approaches. Additionally, we will delineate the role of NHERF1-microRNA (miR)155-suppressor of cytokine signaling (SOCS1)-Src homology 2 (SH2) domain containing inositol polyphosphate 5-phosphatase 1 (SHIP-1) axis in promoting mast cell activation. Given the critical role of mast cell-MRGPRX2 in causing pseudoallergic reactions and chronic inflammation in allergic diseases, elucidation of the mechanisms by which NHERF1 contributes to MRGPRX2-mediated allergic response is of significant scientific and clinical importance. We firmly believe that successful completion of the proposed studies will likely lead to the identification of potential targets of the MRGPRX2 pathway that can provide insights into the future development of drugs for not only pseudoallergic reactions but also other mast cell-mediated inflammatory diseases.


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: 2025 ( Subtotal = $474,415 )
2025	2025	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	2	6/23/2025	NON-COMPETING CONTINUATION	$474,415
														Subtotal = $474,415

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	1	7/5/2024	NEW	$0
2024	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	001	1	7/23/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $460,688 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Allergy and Infectious Diseases Research	000	1	7/12/2023	NEW	$460,688
														Subtotal = $460,688

Grand Total All Awards = $935,103

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NHERF1 regulates MRGPRX2/MrgprB2 responses in mast cells

Award Number: R01AI177305

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/12/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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