Asthma and chronic obstructive pulmonary diseases (COPD) are among the most common debilitating human lung conditions. Airway inflammation in asthma is often typified by an influx of eosinophils, whereas in COPD neutrophils are prominent. Siglec-8 and Siglec-9 are found on non-overlapping cell subsets, with Siglec-8 expressed on human eosinophils, mast cells and basophils, and Siglec-9 expressed on neutrophils, macrophages, NK cells and some B and T cells. Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs, while human Siglec-9 and mouse Siglec-E are orthologs. Engagement of these human Siglecs negatively regulates their cellular activation and survival. HYPOTHESIS: Siglec-8 and Siglec-9 can be targeted to treat lung inflammation by depleting eosinophils and neutrophils, respectively.
AIMS : In close collaboration with Core C and Core D throughout.
Aim 1 proposes experiments to exploit Siglec-8/-F and its ligands for their anti-eosinophil properties in lung inflammation using existing and novel murine models of asthma.
Aim 2 proposes experiments to exploit Siglec-9/-E and its ligands for their anti-neutrophil properties in lung inflammation using existing and novel murine models of COPD and asthma.
Aim 3 proposes to exploit natural endogenous lung ligands for Siglec-8/-F and Siglec-9/-E, identified in Project 3 and characterized by Project 4, for their anti-granulocyte properties using mouse models utilized in Aims 1 and 2. The role of sialyl- and sulfotransferases in the lung in generating Siglec-F ligands will be explored via airway epithelial-specific deletion and overexpression systems. In each Aim we will test nanoparticles developed by Project 2 for their ability to selectively target Siglec-8/-F and Siglec-9/-E in vivo. Finally, to facilitate testing of such agents for future human use, we propose to employ novel humanized mice, developed by Core D, for testing in the asthma and COPD models including a) an eosinophil-specific Siglec-8 knock-in on the Siglec-F null genetic background to directly study human Siglec-8 biology in vivo; and b) a neutrophil-specific Siglec-9 knock-in mouse on the Siglec-E null background and a second transgenic mouse bearing a Siglec-9 V-set lectin domain exon swap for its counterpart on Siglec-E to directiy study Siglec-9 biology in vivo.
We will utilize the best available animal models of asthma and COPD to test the therapeutic consequences of targeting eosinophils and neutrophils for their deletion in vivo via their cell surface siglecs. Additional experiments will define the role of endogenous sialyl- and sulfoltransferases in generating lung epithelial glycan ligands for eosinophil-depleting siglecs and directly explore human siglec targeting in mice.
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