ELUCIDATING AND TARGETING SIGLEC-9 FUNCTION ON MAST CELLS - PROJECT SUMMARY/ABSTRACT MAST CELLS HAVE BEEN R…

Assistance award details

Assistance award identifier

ASST_NON_R01AI185053_075

FAIN

R01AI185053

Recipient

SEATTLE CHILDREN'S HOSPITAL

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$1,225,834

Period

Jul 23, 2025 – Jun 30, 2030

Fiscal year

2025

Place of performance state

WA

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

ELUCIDATING AND TARGETING SIGLEC-9 FUNCTION ON MAST CELLS - PROJECT SUMMARY/ABSTRACT MAST CELLS HAVE BEEN RECOGNIZED AS KEY EFFECTOR CELLS IN URTICARIA, MASTOCYTOSIS, AND ALLERGIC DISEASE. SPECIFICALLY, STUDIES HAVE SHOWN THAT THE DYSREGULATED EXPANSION AND/OR ACTIVATION OF MAST CELLS HAVE DETRIMENTAL CONSEQUENCES IN THESE DISORDERS. MOREOVER, THEY HAVE DRIVEN THE SEARCH FOR EFFECTIVE NEW STRATEGIES TO DOWNMODULATE MAST CELL FUNCTION. DUE TO THEIR IMMUNORECEPTOR TYROSINE-BASED INHIBITORY (ITIM) MOTIFS, PRE- CLINICAL AND CLINICAL STUDIES SUPPORT SIALIC ACID -BINDING IMMUNOGLOBULIN-LIKE LECTINS (SIGLECS) AS AN ATTRACTIVE THERAPEUTIC TARGET TO INHIBIT MAST CELL FUNCTION IN MAST-ASSOCIATED DISORDERS. HOWEVER, CLINICAL TRIALS AIMED AT EVALUATING THE USE OF ANTIBODIES AGAINST SIGLEC-8, ONE OF THE MOST PROMISING INHIBITORY RECEPTORS FOR MAST CELL TARGETING, DID NOT MEET PRIMARY ENDPOINTS FOR TREATMENT OF ATOPIC DERMATITIS AND CHRONIC SPONTANEOUS URTICARIA. THESE DISAPPOINTING RESULTS HIGHLIGHT THE NEED OF OUR PROPOSED STUDIES TO BETTER UNDERSTAND THE BIOLOGY OF SIGLECS AND THEIR LIGANDS IN A COMPLEX DISEASE MICROENVIRONMENT THAT CAN IMPACT SIGLEC ABILITY TO MODULATE MAST CELL FUNCTION. OUR PUBLISHED STUDIES AND PRELIMINARY DATA DEMONSTRATE THAT: 1-SIGLEC-9 CO-ENGAGEMENT WITH THE HIGH AFFINITY RECEPTOR FOR IGE INHIBITS HUMAN PRIMARY MAST CELL ACTIVATION, AND THE SEVERITY OF SYSTEMIC ANAPHYLACTIC REACTIONS; 2-SIGLEC-9 ON MAST CELLS CAN ATTENUATE THE SEVERITY OF ALLERGIC AIRWAY IMMUNOPATHOLOGY; AND 3-SIGLEC- 9 INTERACTIONS WITH ITS LIGANDS IN CIS PROMOTE MAST CELL QUIESCENCE. ACCORDINGLY, THE OVERALL GOAL OF THIS PROPOSAL IS TO TEST THE HYPOTHESIS THAT SIGLEC-9 AND ITS LIGANDS PLAY A CRITICAL ROLE IN MAST CELL HOMEOSTASIS, AND THAT SIGLEC- 9 CAN BE TARGETED TO REDUCE THE SEVERITY OF MAST CELL-ASSOCIATED DISORDERS. IN AIM 1, WE WILL INVESTIGATE HOW SIGLEC-9 LIGAND METABOLISM CAN MODULATE HUMAN MAST CELL FUNCTION IN VITRO AND IN MOUSE MODELS OF SYSTEMIC ANAPHYLAXIS. IN AIM 2, W