Asthma and chronic obstructive pulmonary disease (COPD) involve accumulation and activation of inflammatory cells in the lung. Inflammation in asthma is marked by the influx of eosinophils, mast cells, and CD4+ T-cells whereas COPD is marked by the influx of neutrophils, macrophages and CD8+ T-cells. Members of the Siglec family of glycan binding proteins (sialic acid-binding immunoglobulin-like lectins) are expressed selectively on subsets of inflammatory cells: Siglec-8 on allergic inflammatory cells (eosinophils, mast cells and basophils) and Siglec-9 on monocytes, neutrophils, and some T-cells. Both Siglec-8 and Siglec-9 suppress inflammation. Crosslinking siglecs on inflammatory cells inhibits release of proinflammatory mediators, enhances release of anti-inflammatory mediators, or induces apoptosis/death, depending on the inflammatory cell type. HYPOTHESIS: Glycoconjugate ligands (siglec counter-receptors) in the lung, consisting of endogenous glycoproteins and/or glycolipids, engage Siglec-8 on incoming allergic inflammatory cells and Siglec 9 on COPD inflammatory cells as a feedback mechanism to limit ongoing inflammatory responses.
AIMS : This project will isolate, identify and characterize the human lung counter- receptors for Siglec-8 and Siglec-9. Glycoconjugates (glycoproteins and/or glycolipids) will be extracted from human lung and the major siglec-binding entities will be isolated by conventional, lectin, and Siglec affinity chromatography. The resulting siglec-interacting molecules will be analyzed by mass spectrometry in collaboration with Project 4 of this program. The expression of counter-receptors will be characterized on cultured human lung epithelial and/or endothelial cells and the enzymes responsible for their biosynthesis will be determined by RNAi knockdown. Siglec counter-receptor expression will be compared on normal and diseased human nasal epithelium. The properties of counter-receptors on mouse lung epithelium will be compared with those from human lung. Knowledge of the endogenous human lung counter-receptors for Siglec-8 and Siglec-9 may provide insights useful in understanding the progression of lung inflammatory diseases and may provide improved lead structures for anti-inflammatory therapeutics.
Asthma and COPD, lung diseases that cause extensive illness and death, involve infiltration of damaging inflammatory cells. Normally, sugar molecules in the lung engage complementary molecules on inflammatory cells, signaling them to halt and limiting tissue damage. This project will define those anti-inflammatory sugar molecules in an effort to better understand lung inflammatory diseases and to find new ways to treat them.
|Janssen, William J; Stefanski, Adrianne L; Bochner, Bruce S et al. (2016) Control of lung defence by mucins and macrophages: ancient defence mechanisms with modern functions. Eur Respir J 48:1201-1214|
|McBride, Ryan; Paulson, James C; de Vries, Robert P (2016) A Miniaturized Glycan Microarray Assay for Assessing Avidity and Specificity of Influenza A Virus Hemagglutinins. J Vis Exp :|
|Schnaar, Ronald L (2016) Gangliosides of the Vertebrate Nervous System. J Mol Biol 428:3325-36|
|Gicheva, Nadezhda; Macauley, Matthew S; Arlian, Britni M et al. (2016) Siglec-F is a novel intestinal M cell marker. Biochem Biophys Res Commun 479:1-4|
|Schleimer, Robert P; Schnaar, Ronald L; Bochner, Bruce S (2016) Regulation of airway inflammation by Siglec-8 and Siglec-9 sialoglycan ligand expression. Curr Opin Allergy Clin Immunol 16:24-30|
|Schnaar, Ronald L (2016) Glycobiology simplified: diverse roles of glycan recognition in inflammation. J Leukoc Biol 99:825-38|
|Cheng, Chu-Wen; Chou, Chi-Chi; Hsieh, Hsiao-Wu et al. (2015) Efficient Mapping of Sulfated Glycotopes by Negative Ion Mode nanoLC-MS/MS-Based Sulfoglycomic Analysis of Permethylated Glycans. Anal Chem 87:6380-8|
|Bochner, Bruce S; Zimmermann, Nives (2015) Role of siglecs and related glycan-binding proteins in immune responses and immunoregulation. J Allergy Clin Immunol 135:598-608|
|Kiwamoto, Takumi; Katoh, Toshihiko; Evans, Christopher M et al. (2015) Endogenous airway mucins carry glycans that bind Siglec-F and induce eosinophil apoptosis. J Allergy Clin Immunol 135:1329-40.e1-9|
|Schnaar, Ronald L (2015) Glycans and glycan-binding proteins in immune regulation: A concise introduction to glycobiology for the allergist. J Allergy Clin Immunol 135:609-15|
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