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.
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.
|Schommer, Nina N; Muto, Jun; Nizet, Victor et al. (2014) Hyaluronan breakdown contributes to immune defense against group A Streptococcus. J Biol Chem 289:26914-21|
|Lin, Ann E; Autran, Chloe A; Espanola, Sophia D et al. (2014) Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. J Infect Dis 209:389-98|
|Mooij, H L; Cabrales, P; Bernelot Moens, S J et al. (2014) Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function. J Am Heart Assoc 3:e001274|
|Padler-Karavani, Vered; Hurtado-Ziola, Nancy; Chang, Yung-Chi et al. (2014) Rapid evolution of binding specificities and expression patterns of inhibitory CD33-related Siglecs in primates. FASEB J 28:1280-93|
|Muto, Jun; Morioka, Yasuhide; Yamasaki, Kenshi et al. (2014) Hyaluronan digestion controls DC migration from the skin. J Clin Invest 124:1309-19|
|Xu, Ding; Esko, Jeffrey D (2014) Demystifying heparan sulfate-protein interactions. Annu Rev Biochem 83:129-57|
|Thacker, Bryan E; Xu, Ding; Lawrence, Roger et al. (2014) Heparan sulfate 3-O-sulfation: a rare modification in search of a function. Matrix Biol 35:60-72|
|Chang, Yung-Chi; Olson, Joshua; Beasley, Federico C et al. (2014) Group B Streptococcus engages an inhibitory Siglec through sialic acid mimicry to blunt innate immune and inflammatory responses in vivo. PLoS Pathog 10:e1003846|
|van Sorge, Nina M; Cole, Jason N; Kuipers, Kirsten et al. (2014) The classical lancefield antigen of group a Streptococcus is a virulence determinant with implications for vaccine design. Cell Host Microbe 15:729-40|
|Zhang, Bing; Xiao, Wenyuan; Qiu, Hong et al. (2014) Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia. J Clin Invest 124:209-21|
Showing the most recent 10 out of 21 publications