This renewal proposal for our Program Project Grant continues to employ an interdisciplinary approach to study the functions of protein-glycan interactions in the vascular system. The three thematically related projects are led by investigators with complementary expertise and a strong published record of collaborative research. Project 1 uses gene-targeted mice to study the interplay of adhesion and signaling molecules in the vasculature. The emphasis is on processes that regulate the interactions of selectins with their glycoconjugate ligands, a critical early response during inflammation and thrombosis. Mice with altered expression of selectins, selectin ligands, or signaling proteins will be studied. Project 2 studies the interactions of galectins with leukocytes. Major themes include the defining the glycan structures recognized by each galectin, the signaling mechanisms for the novel exposure of phosphatidylserine on activated neutrophils without apoptosis, and the biological roles of galectins in regulating inflammation in vivo. Project 3 studies how the 0-glycoprotein podoplanin maintains separated blood and lymphatic vessels, how mixing of blood and lymphatic vessels contributes to disease, and how 0-glycosylation regulates the functions of podoplanin in vitro and in vivo. There is unusually high synergy among the projects that results from the intellectually overlapping themes and the sharing of reagents and methods. An administrative core cements the interactions, in particular through maintenance of a server for data exchange among the projects and through computer support for processing images and other complex data. The data obtained will enhance our understanding of the functions of lectins and glycoconjugates during inflammation, thrombosis, and vascular development. This information may suggest new approaches to treat heart attacks, strokes, and other cardiovascular disorders.

Public Health Relevance

This interdisciplinary project studies how interactions of proteins with complex carbohydrates regulate the functions of blood cells, blood vessels, and a distinct set of vessels called lymphatics. The research may lead to new treatments for heart attacks, strokes, cancer, and other diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL085607-07
Application #
8274713
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Sarkar, Rita
Project Start
2006-07-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
7
Fiscal Year
2012
Total Cost
$1,733,687
Indirect Cost
$506,902
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Herzog, Brett H; Fu, Jianxin; Xia, Lijun (2014) Mucin-type O-glycosylation is critical for vascular integrity. Glycobiology 24:1237-41
Sreeramkumar, Vinatha; Adrover, José M; Ballesteros, Ivan et al. (2014) Neutrophils scan for activated platelets to initiate inflammation. Science 346:1234-8
Stowell, Sean R; Arthur, Connie M; McBride, Ryan et al. (2014) Microbial glycan microarrays define key features of host-microbial interactions. Nat Chem Biol 10:470-6
Liu, Xiaolei; Pasula, Satish; Song, Hoogeun et al. (2014) Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function. Sci Signal 7:ra97
Wan, Xiang; Sato, Hidetaka; Miyaji, Hiromasa et al. (2013) Fucosyltransferase VII improves the function of selectin ligands on cord blood hematopoietic stem cells. Glycobiology 23:1184-91
Herzog, Brett H; Fu, Jianxin; Wilson, Stephen J et al. (2013) Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2. Nature 502:105-9
Shao, Bojing; Yago, Tadayuki; Coghill, Phillip A et al. (2012) Signal-dependent slow leukocyte rolling does not require cytoskeletal anchorage of P-selectin glycoprotein ligand-1 (PSGL-1) or integrin *L*2. J Biol Chem 287:19585-98
Miner, Jonathan J; Shao, Bojing; Wang, Ying et al. (2011) Cytoplasmic domain of P-selectin glycoprotein ligand-1 facilitates dimerization and export from the endoplasmic reticulum. J Biol Chem 286:9577-86
Shao, Bojing; Wahrenbrock, Mark G; Yao, Longbiao et al. (2011) Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 118:4015-23
Cerliani, Juan P; Stowell, Sean R; Mascanfroni, Ivan D et al. (2011) Expanding the universe of cytokines and pattern recognition receptors: galectins and glycans in innate immunity. J Clin Immunol 31:10-21

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