During inflammation, flowing leukocytes roll on vascular surfaces through interactions of selectins with their glycosylated ligands. Activated endothelial cells express P-selectin and E-selectin. Their major ligands on leukocytes are P-selectin glycoprotein ligand-1 (PSGL-1), which binds to P- and E-selectin, and CD44, which binds to E-selectin. Data obtained during the previous funding period demonstrated that the organization of selectins and their ligands on cell surfaces has major impact on functions. We hypothesize that selectins and their ligands form homodimers through self-associations of their transmembrane domains. They localize in specialized membrane regions (e.g. microvilli, clathrin-coated pits, or lipid rafts) through interactions of their transmembrane or cytoplasmic domains with lipids, adaptor proteins, or cytoskeletal elements. Dimerization and membrane-domain targeting cooperate to enhance adhesive and signaling functions. We propose to test these hypotheses by making monomeric and dimeric forms of P-selectin, E-selectin, PSGL-1, and CD44 that do or do not target to lipid rafts or clathrin-coated pits. Other variants will test interactions with cytoskeletal and signaling proteins. Cells from knockout mice lacking signaling components will also be used. These tools will probe how cells organize selectins and their ligands to regulate leukocyte adhesion and signaling in vitro and in vivo. Because selectins and their ligands are major contributors to pathological inflammation and thrombosis, understanding how they function in their cellular environments may suggest new opportunities for therapeutic intervention.

Public Health Relevance

White blood cells (leukocytes) combat infection and repair tissue injury. To do this, they must move from blood into the affected tissues, a process that begins when circulating leukocytes attach to blood vessel surfaces through """"""""adhesion receptors."""""""" This project addresses how leukocytes and cells lining blood vessels control the display and function of these receptors. Because excessive recruitment of leukocytes contributes to many diseases, including heart attacks and strokes, understanding how cells regulate adhesion receptors may suggest new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034363-27
Application #
8243638
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Sarkar, Rita
Project Start
1987-09-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
27
Fiscal Year
2012
Total Cost
$543,742
Indirect Cost
$210,158
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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
Zhang, Nan; Liu, Zhenghui; Yao, Longbiao et al. (2016) P-Selectin Expressed by a Human SELP Transgene Is Atherogenic in Apolipoprotein E-Deficient Mice. Arterioscler Thromb Vasc Biol 36:1114-21
Shao, Bojing; Yago, Tadayuki; Setiadi, Hendra et al. (2015) O-glycans direct selectin ligands to lipid rafts on leukocytes. Proc Natl Acad Sci U S A 112:8661-6
Pruenster, Monika; Kurz, Angela R M; Chung, Kyoung-Jin et al. (2015) Extracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion. Nat Commun 6:6915
Yago, Tadayuki; Tsukamoto, Hiroki; Liu, Zhenghui et al. (2015) Multi-Inhibitory Effects of A2A Adenosine Receptor Signaling on Neutrophil Adhesion Under Flow. J Immunol 195:3880-9
McEver, Rodger P (2015) Selectins: initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res 107:331-9
Yago, Tadayuki; Petrich, Brian G; Zhang, Nan et al. (2015) Blocking neutrophil integrin activation prevents ischemia-reperfusion injury. J Exp Med 212:1267-81
Wang, Ying; Yago, Tadayuki; Zhang, Nan et al. (2014) Cytoskeletal regulation of CD44 membrane organization and interactions with E-selectin. J Biol Chem 289:35159-71
Sreeramkumar, Vinatha; Adrover, José M; Ballesteros, Ivan et al. (2014) Neutrophils scan for activated platelets to initiate inflammation. Science 346:1234-8
Zhang, Yan; Jiang, Ning; Zarnitsyna, Veronika I et al. (2013) P-selectin glycoprotein ligand-1 forms dimeric interactions with E-selectin but monomeric interactions with L-selectin on cell surfaces. PLoS One 8:e57202

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