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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107151-04
Application #
8669107
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$371,812
Indirect Cost
$142,082
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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