Cell surface glycans and complementary glycan binding proteins are intimately involved in inflammatory processes. Members of this Program team and others discovered that certain members of the siglec family of glycan binding proteins are inhibitors of inflammation. This Lung Inflammatory Disease Program of Excellence in Glycosciences (LID-PEG) focuses on the anti-inflammatory functions of siglecs and their glycan counter-receptors (ligands) in moderating ongoing inflammation in the lung. THEME: Specific glycans expressed on lung tissues engage complementary glycan binding proteins (Siglec-8, Siglec-9, Siglec-1) on inflammatory cells to limit lung inflammation. Knowledge of the glycan structures and glycan binding proteins involved, the control of their expression, and the mechanisms responsible for translating glycan engagement into regulation of the inflammatory response will provide new insights into the progression of inflammatory lung diseases. Synthetic glycan-decorated nanoparticles and antibodies that target glycan binding proteins on inflammatory cells will limit inflammatory damage. The insights gained may lead to novel diagnostic tools and therapeutic compositions that treat inflammatory diseases of the lung and other tissues relevant to the goals of the NHLBI. Four closely integrated Projects and two Cores at three major glycobiology centers will coordinate efforts to reach the Project goals: Project 1, """"""""Treating lung inflammation by targeting siglecs"""""""" (B. Bochner, Johns Hopkins);Project 2, """"""""Siglec-targeted nanoparticles for lung and cardiovascular disease"""""""" (J. Paulson, Scripps);Project 3, """"""""Human lung counter-receptors for Siglec-8 and Siglec-9"""""""" (R. Schnaar, Johns Hopkins);Project 4, """"""""Regulated expression of siglec counter-receptors"""""""" (M. Tiemeyer, CCRC/U. Georgia);Core C, """"""""Shared Resources Core: Carbohydrate Synthesis"""""""" (J. Paulson, Scripps);and Core D, """"""""Inflammatory Animal Models Core"""""""" (Z. Zhu, Johns Hopkins). The Program is supported by an Administrative Core (Core A) and a Skills Development Core (Core B) that provides trainees with diverse experiences at the three centers. This Program will provide novel insights into the glycosciences of lung inflammatory diseases.

Public Health Relevance

Asthma and Chronic Obstructive Pulmonary Disease (COPD), lung diseases that cause extensive illness and death, involve infiltration of damaging inflammatory cells. Normally, sugar molecules in the lung engage complementary sugar binding molecules on inflammatory cells, signaling them to halt and limiting tissue damage. This project defines anti-inflammatory sugar molecules and uses them to develop new treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107151-02
Application #
8289349
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Program Officer
Gail, Dorothy
Project Start
2011-07-01
Project End
2018-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$2,207,463
Indirect Cost
$479,779
Name
Johns Hopkins University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
O'Sullivan, Jeremy A; Bochner, Bruce S (2017) Eosinophils and eosinophil-associated diseases: An update. J Allergy Clin Immunol :
Yu, Huifeng; Gonzalez-Gil, Anabel; Wei, Yadong et al. (2017) Siglec-8 and Siglec-9 binding specificities and endogenous airway ligand distributions and properties. Glycobiology 27:657-668
O'Sullivan, Jeremy A; Carroll, Daniela J; Cao, Yun et al. (2017) Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells. J Allergy Clin Immunol :
Carroll, Daniela J; O'Sullivan, Jeremy A; Nix, David B et al. (2017) Sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8) is an activating receptor mediating ?2-integrin-dependent function in human eosinophils. J Allergy Clin Immunol :
Guo, Hongbo; de Vries, Erik; McBride, Ryan et al. (2017) Highly Pathogenic Influenza A(H5Nx) Viruses with Altered H5 Receptor-Binding Specificity. Emerg Infect Dis 23:220-231
Lou, Hongfei; Lu, Jingning; Choi, Eun Byul et al. (2017) Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway. J Immunol 198:2543-2555
Peng, Wenjie; Paulson, James C (2017) CD22 Ligands on a Natural N-Glycan Scaffold Efficiently Deliver Toxins to B-Lymphoma Cells. J Am Chem Soc 139:12450-12458
Schnaar, Ronald L; Lee, Yuan C (2017) Discoveries of the structures of sialic acid and CMP-sialic acid (1957-1960): A letter from Saul Roseman. Glycobiology :
Wu, Nicholas C; Xie, Jia; Zheng, Tianqing et al. (2017) Diversity of Functionally Permissive Sequences in the Receptor-Binding Site of Influenza Hemagglutinin. Cell Host Microbe 21:742-753.e8
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

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