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 #
5P01HL085607-09
Application #
8677944
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
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$1,699,358
Indirect Cost
$533,863
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Mehta-D'souza, Padmaja; Klopocki, Arkadiusz G; Oganesyan, Vaheh et al. (2017) Glycan Bound to the Selectin Low Affinity State Engages Glu-88 to Stabilize the High Affinity State under Force. J Biol Chem 292:2510-2518
Panicker, Sumith R; Mehta-D'souza, Padmaja; Zhang, Nan et al. (2017) Circulating soluble P-selectin must dimerize to promote inflammation and coagulation in mice. Blood 130:181-191
Liu, Zhenghui; Yago, Tadayuki; Zhang, Nan et al. (2017) L-selectin mechanochemistry restricts neutrophil priming in vivo. Nat Commun 8:15196
Bergstrom, Kirk; Liu, Xiaowei; Zhao, Yiming et al. (2016) Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice. Gastroenterology 151:152-164.e11
Rahman, H N Ashiqur; Wu, Hao; Dong, Yunzhou et al. (2016) Selective Targeting of a Novel Epsin-VEGFR2 Interaction Promotes VEGF-Mediated Angiogenesis. Circ Res 118:957-969
Liu, Zhenghui; Zhang, Nan; Shao, Bojing et al. (2016) Replacing the Promoter of the Murine Gene Encoding P-selectin with the Human Promoter Confers Human-like Basal and Inducible Expression in Mice. J Biol Chem 291:1441-7
Brazil, Jennifer C; Sumagin, Ronen; Cummings, Richard D et al. (2016) Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation. Am J Pathol 186:297-311
Chen, Wei-Sheng; Cao, Zhiyi; Sugaya, Satoshi et al. (2016) Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3. Nat Commun 7:11302
Dong, Yunzhou; Wu, Hao; Rahman, H N Ashiqur et al. (2016) Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest 126:1607
Crosswhite, Patrick L; Podsiadlowska, Joanna J; Curtis, Carol D et al. (2016) CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J Clin Invest 126:2254-66

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