We propose collaborative studies of glycan modulation of inflammatory responses involving myeloid cells, endothelial biology, innate immunity and host-microbial interactions - using genetically-modified mice and bacteria. A particular focus is on roles of two major types of anionic glycans: sialic acids (Sias) and the glycosaminoglycans (GAGs), hyaluronan (HA), heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (CS/DS). Specific glycan-binding proteins differentially recognize these glycans, mediating many important functions in inflammation. Many physiologic and pathological roles of such glycans are not fully evident in cultured cells, and some such as roles in inflammation must be explored in an intact vertebrate. An underlying theme of this PEG is state-of-the-art genetic manipulation of these glycans, and/or their cognate binding proteins in the mouse. Our highly interactive team of experts is support by state-of-the-art Core facilities with many opportunities for intellectual and practical collaborations and synergies. Project 1 will elucidate functions of activatory and Arg-mutated forms of CD33-related Siglecs on myeloid cells, which likely represent evolutionary adjustments to pathogens expressing Sias. Project 2 will study innate immune functions of myeloid cells challenged by microbes that either mimic host Sias or GAGs, or which produce glycosidases targeting them. Project 3 studies sulfation patterns of HS and CS/DS chains in regulating myeloid cells and endothelial biology. Project 4 investigates how HA catabolism acts during inflammation to modulate the innate immune response. We proposed five cores to support the research and training objectives ofthe PEG: Core A, a Glycosciences Skills Development Core for recruitment and training of Fellows;Core B, a shared resource for Glycan Synthesis and Analysis;Core C, Administrative and Mouse Management Core;Core D, Histopathology;and Core E, Hematology and Clinical Chemistry. The overall objective is to understand the multi-faceted roles of Sias and GAGs in the biology of inflammation, enhance resources for glycosciences, and to identify and train the best postdoctoral fellows who have a strong potential to develop into an outstanding independent investigators working in areas relevant to NHLBI.

Public Health Relevance

This multidisciplinary partnership will bring together experts and new investigators to focus on glycans and glycan-binding proteins in innate immunity, revealing many important functions in health and disease. The program will also create resources for glycosciences and nurture and train a cadre of new investigators, who will sustain and advance the future applications of glycosciences to heart, lung, and blood research.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Program Officer
Sarkar, Rita
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Other Basic Sciences
Schools of Medicine
La Jolla
United States
Zip Code
Gordts, Philip L S M; Nock, Ryan; Son, Ni-Huiping et al. (2016) ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest 126:2855-66
Varki, Ajit (2016) Biological Roles of Glycans. Glycobiology :
Yamaguchi, Masaya; Hirose, Yujiro; Nakata, Masanobu et al. (2016) Evolutionary inactivation of a sialidase in group B Streptococcus. Sci Rep 6:28852
Secundino, Ismael; Lizcano, Anel; Roupé, K Markus et al. (2016) Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation. J Mol Med (Berl) 94:219-33
Thacker, Bryan E; Seamen, Emylie; Lawrence, Roger et al. (2016) Expanding the 3-O-Sulfate Proteome--Enhanced Binding of Neuropilin-1 to 3-O-Sulfated Heparan Sulfate Modulates Its Activity. ACS Chem Biol 11:971-80
Zhang, Ling-Juan; Sen, George L; Ward, Nicole L et al. (2016) Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-β Production by Epidermal Keratinocytes during Skin Injury. Immunity 45:119-30
Schwarz, Flavio; Springer, Stevan A; Altheide, Tasha K et al. (2016) Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline. Proc Natl Acad Sci U S A 113:74-9
Sato, Emi; Muto, Jun; Zhang, Ling-Juan et al. (2016) The Parathyroid Hormone Second Receptor PTH2R and its Ligand Tuberoinfundibular Peptide of 39 Residues TIP39 Regulate Intracellular Calcium and Influence Keratinocyte Differentiation. J Invest Dermatol 136:1449-59
Miles, L A; Baik, N; Lighvani, S et al. (2016) Deficiency of Plasminogen Receptor, Plg-RKT, Causes Defects in Plasminogen Binding and Inflammatory Macrophage Recruitment in vivo. J Thromb Haemost :
Zaiss, Anne K; Foley, Erin M; Lawrence, Roger et al. (2016) Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo. J Virol 90:412-20

Showing the most recent 10 out of 59 publications