instmctions): 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 ainway 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 directiy 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.
|Stowell, Sean R; Arthur, Connie M; McBride, Ryan et al. (2014) Microbial glycan microarrays define key features of host-microbial interactions. Nat Chem Biol 10:470-6|
|Kawasaki, Norihito; Rillahan, Cory D; Cheng, Tan-Yun et al. (2014) Targeted delivery of mycobacterial antigens to human dendritic cells via Siglec-7 induces robust T cell activation. J Immunol 193:1560-6|
|Kiwamoto, Takumi; Brummet, Mary E; Wu, Fan et al. (2014) Mice deficient in the St3gal3 gene product *2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation. J Allergy Clin Immunol 133:240-7.e1-3|
|Macauley, Matthew S; Crocker, Paul R; Paulson, James C (2014) Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol 14:653-66|
|Cho, Seok Hyun; Oh, Sun Young; Lane, Andrew P et al. (2014) Regulation of nasal airway homeostasis and inflammation in mice by SHP-1 and Th2/Th1 signaling pathways. PLoS One 9:e103685|
|Fang, Ping; Zhou, Li; Zhou, Yuqi et al. (2014) Immune modulatory effects of IL-22 on allergen-induced pulmonary inflammation. PLoS One 9:e107454|
|Nix, David B; Kumagai, Tadahiro; Katoh, Toshihiko et al. (2014) Improved in-gel reductive ?-elimination for comprehensive O-linked and sulfo-glycomics by mass spectrometry. J Vis Exp :e51840|
|Rillahan, Cory D; Macauley, Matthew S; Schwartz, Erik et al. (2014) Disubstituted Sialic Acid Ligands Targeting Siglecs CD33 and CD22 Associated with Myeloid Leukaemias and B Cell Lymphomas. Chem Sci 5:2398-2406|
|Kiwamoto, Takumi; Katoh, Toshihiko; Tiemeyer, Michael et al. (2013) The role of lung epithelial ligands for Siglec-8 and Siglec-F in eosinophilic inflammation. Curr Opin Allergy Clin Immunol 13:106-11|
|Rillahan, Cory D; Schwartz, Erik; Rademacher, Christoph et al. (2013) On-chip synthesis and screening of a sialoside library yields a high affinity ligand for Siglec-7. ACS Chem Biol 8:1417-22|
Showing the most recent 10 out of 15 publications