Infiltration and activation of inflammatory leukocytes drive the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD), two lung inflammatory diseases (LIDs) that produce signiflcant human suffering and consume considerable medical resources. Eosinophils and neutrophils express different members of the siglec family of glycan binding proteins, and siglec activation on either cell population suppresses lung inflammation by inducing granulocyte apoptosis. In humans, eosinophils express Siglec-8 and neutrophils express Siglec-9. Candidate ligands that bind these siglecs were identified through in vitro glycan array screening, predicting key structural features to be expected of potent, endogenous siglec counter-receptors. However, endogenous glycan counter-receptors for Siglec-8 and -9, as well as the proteins or lipids to which they are attached remain to be determined. Furthermore, the mechanisms that control the expression of siglec counter-receptors are unknown, but, if understood, could be invoked to facilitate granulocyte apoptosis through enhanced counter-receptor synthesis. HYPOTHESIS: The expression of endogenous siglec counter-receptors is regulated by innate signaling mechanisms that coordinate the presentation of potent pro- and anti-infiammatory glycans.
AIMS : The total glycome of human lung tissue and isolated cell types will be characterized by mass spectrometry and orthogonal analytic approaches to define the full diversity of potential siglec counter-receptor configurations. In collaboration with Proiect 3 (Schnaar), proteomic analysis of affinity-purified materials extracted from human lung tissue will identify protein carriers that present siglec counter-receptors. Emerging evidence reveals crosstalk between siglec and toll-like receptor signaling, indicating the existence of innate regulatory networks for controlling glycan expression. Therefore, dynamic changes in cell-specific glycan expression will be assessed following cytokine or Toll-like receptor agonist administration to isolated and co-cultured lung cell types.
The aims are designed to identify the diversity of endogenous counter-receptors for siglecs and to deconvolute the signaling pathways that regulate counter-receptor expression in order to enhance the development of potent therapeutics.

Public Health Relevance

This project will identify glycan structures that possess anti-inflammatory activity in lung inflammatory diseases (LID) such as asthma and chronic obstructive pulmonary disease. The mechanism by which lung tissue and leukocytes normally control the synthesis of these anti-inflammatory glycans will also be studied in order to enhance their production and thereby reduce LID severity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107151-03
Application #
8477256
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$337,560
Indirect Cost
$477
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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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

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