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Unraveling FcepsilonRI-independent regulation of mast cell functions by the ITCH ubiquitin ligase

Award Number: R21AI193590
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: 08/06/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Unraveling FcepsilonRI-independent regulation of mast cell functions by the ITCH ubiquitin ligase - PROJECT SUMMARY Mast cells (MC) are innate immune cells that occupy a unique niche in tissues in which they reside as long-lived perpetrators of immunoglobulin E (IgE)-mediated hypersensitivity and many other inflammatory responses. We have shown that MC initiate skin and lung inflammation through the rapid release of inflammatory mediators, including cell-attracting chemokines. This occurs, in part, in a FcεRI-independent manner through ligation of receptors (R) for a bioactive signaling lipid, sphingosine-1-phosphate (S1P), and for lipopolysaccharide (LPS), an endotoxin present in most environmental antigens (Ag) penetrating the body. Engagement of MC-stimulating R signalosomes encompasses kinase phosphorylation/activation, ultimately leading to transcription factor signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activation, linked to chemokine release. Little is known about the regulatory pathways halting MC activation to restore homeostasis. One of the mechanisms limiting inflammation and MC functions is through ubiquitination. E3 ubiquitin ligases attach ubiquitin chains to protein substrates for rapid removal of unwanted or damaged proteins and have been described as negative regulators of IgE-mediated signaling and subsequent mediator release by MC. Deficiency of the E3 ubiquitin ligase ITCH results in systemic inflammation of the mucosal surfaces, such as skin and lungs. Similar findings are described in human patients, including clinical manifestations of atopy. Thus, there is an unmet need to understand how ITCH regulates inflammation and MC biology. Our preliminary data show that primary MC express ITCH, which is predicted to interact with several MC-restricted enzymes. Moreover, ITCH negatively regulates inflammation by controlling the ubiquitin-editing enzyme TNF Alpha Induced Protein 3 (Tnfaip3/A20) function, thus NF-κB activation. ITCH is also predicted to interact with Bruton’s tyrosine kinase (BTK), an enzyme involved in MC activation that we also found is essential to STAT3 activation downstream of S1P signaling in MC (our preliminary data). The objectives of this application are to determine how ITCH affects MC intrinsic function in vitro and in vivo, and to identify ITCH-regulated targets in these pathways using primary MC. We anticipate that our proposed studies will provide novel mechanistic data delineating how ITCH, an E3 ubiquitin ligase, can regulate signaling mechanisms driving skin and lung inflammation and MC functions. These mechanistic insights will identify an actionable inflammation-enabling molecular target in ITCH as a regulator of MC reactivity, with the potential to prevent the onset of inflammation and progress to a diseased state.


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: 2026 ( Subtotal = $186,250 )
2026	2026	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	000	2	8/21/2026	NON-COMPETING CONTINUATION	$186,250
														Subtotal = $186,250

Issue Date FY: 2025 ( Subtotal = $223,500 )
2025	2025	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Allergy and Infectious Diseases Research	000	1	8/5/2025	NEW	$223,500
														Subtotal = $223,500

Grand Total All Awards = $409,750

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Unraveling FcepsilonRI-independent regulation of mast cell functions by the ITCH ubiquitin ligase

Award Number: R21AI193590

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: 08/06/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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