P01 HL107151 NIH/NHLBI -Ronald Schnaar (PI), Johns Hopkins University School of Medicine
Bochner Role: PI - Project 1 “Treating lung inflammation by targeting siglecs”
This project defines anti-inflammatory sugar molecules and uses them to develop new treatments for lung diseases, employing among other approaches newly developed humanized eosinophil-specific Siglec-8 knock-in mice.
Asthma remains among the most common debilitating human lung conditions. Airway inflammation in asthma is often typified by Type 2 inflammation. Siglec-8 is expressed on human eosinophils, mast cells and basophils. Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs. Engagement of these siglecs negatively regulates their cellular activation and survival. Our overarching hypothesis is that Siglec-8 can be targeted to treat lung inflammation by depleting eosinophils and inhibiting mast cells.
In close collaboration with other groups involved in this program project grant, we are performing experiments to exploit Siglec-8/-F and its ligands for their anti-eosinophil and anti-mast cell properties in lung inflammation using existing and novel murine models of asthma. We plan to exploit natural endogenous lung ligands for Siglec-8/-F, identified and characterized by colleagues at Johns Hopkins University and the University of Georgia’s Complex Carbohydrate Research Center, for their anti-inflammatory properties using mouse models. 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. We will test nanoparticles developed by our collaborators at The Scripps Institute for their ability to selectively target Siglec-8/-F in vivo. Finally, to facilitate testing of such agents for future human use, we will employ novel humanized mice, developed by collaborators at Yale, for testing in murine asthma models including eosinophil and/or mast cell-specific Siglec-8 knock-in on the Siglec-F null genetic background to directly study human Siglec-8 biology in vivo.
Pathways for control of eosinophilic lung inflammation via sugars found on the mucin Muc5b. Eosinophils (expressing Siglec-F) are preferentially recruited into the airways during many forms of asthma and other eosinophilic lung diseases (panel A). Once in the airways, selective binding to Siglec-F of specific sugars displayed on Muc5b triggers eosinophil death, helping to eliminate these troublesome cells from the airway (panel B). Artwork provided by Jacqueline Schaffer.