OVERALL ABSTRACT Mast cells and eosinophils are essential effector cells in both acute and chronic allergic inflammatory responses. The overall goal of this Program is to exploit eosinophil and mast cell Siglecs (sialic acid binding, immunoglobulin-like lectins) to prevent or treat immediate allergic reactions and chronic allergic inflammation. The overarching hypothesis is that specific mAbs, endogenous tissue glycans, or synthetic ligand analogs, can specifically and selectively engage complementary glycan binding Siglecs (CD33, Siglec-6, and Siglec-8) on eosinophils and/or mast cells to prevent or limit IgE-dependent and IgE-independent eosinophil and mast cell- related allergic responses. This application focuses on the role of three mast cell and eosinophil Siglecs that we hypothesize provide ideal targets for dampening allergic effector cell responses in a variety of acute and chronic allergy-related disorders. Dr. Bruce Bochner will serve as the PI of Project 1 (Defining Siglec-6 and Siglec-8 function on effector cells of allergic diseases as well as Core A (Administration) and Core B (Human mast cell and tissue acquisition core). Dr. James Paulson will serve as the PI of Project 2 (Siglec-targeted nanoparticles for treating mast cell mediated allergic disease) while Dr. Ronald Schnaar will serve as the PI of Project 3 (Human siglec ligands control mast cell and eosinophil mediated inflammation). This is a Program team with a proven track record of productivity and synergy. This application includes projects that examine Siglec/eosinophil/mast cell pathways from various perspectives including pharmacology, biochemistry, cell signaling, glycobiology, and cellular and molecular biology, using in vitro experimentation and in vivo humanized models. The majority of the proposed research utilizes human material including primary human cells and biologic samples, along with animal models involving humanized mast cell mice and novel knock-in strains of mice expressing human Siglecs of interest to provide more in-depth hypothesis testing on mechanisms and outcomes that cannot yet be assessed with human research. Each Project provides numerous elements of novelty ranging from human Siglec knock-in mice to development of unique reagents for targeting specific Siglecs to discovery of endogenous human tissue ligands for specific Siglecs.
OVERALL PROGRAM NARRATIVE The goal of this program is to identify new molecular and cellular pathways to control allergic inflammation with implications for enhanced understanding and improved treatments for asthma, allergy, and immune disorders of the skin and gastrointestinal tract. This experienced team discovered that members of the ?Siglec? family of glycan binding proteins can be exploited to suppress allergic inflammation, leading to the hypothesis that natural or synthetic glycans can engage complementary glycan binding proteins (Siglec-3/CD33, Siglec-6, and Siglec-8) on eosinophils and mast cells to prevent or limit allergic damage. Knowledge of the glycan structures and glycan binding proteins involved, the control of their expression, and the mechanisms responsible for translating glycan engagement into cell signaling will be leveraged to provide new insights into the pathophysiology and novel approaches for treatment of allergic diseases.
