Oklahoma Medical Research Foundation (OMRF)

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In my lab, we study how circulating blood cells attach to blood vessel surfaces at sites of tissue injury or infection. Substances released at these sites direct the endothelial cells that line blood vessels to display “adhesion molecules.” These molecules enable circulating white blood cells, or leukocytes, to roll along the vessel surface. The rolling cells then slow to a stop and then crawl between the endothelial cells into the tissues, where they destroy invading microbes. This process is known as inflammation. Similarly, circulating platelets use adhesion molecules to roll along tissues that are exposed when blood vessels are disrupted. The platelets then stop and form clumps to slow hemorrhage and promote blood clotting. Inflammation and blood clotting are often linked. Indeed, leukocytes sometimes roll on and then stick to blood platelets. Excessive inflammation and blood clotting contribute towards many diseases, including heart attacks, stroke, dysfunction of transplanted organs, deep vein thrombosis, and sickle cell crisis.

Three adhesion molecules, called selectins, direct the initial rolling of leukocytes on endothelial cells and platelets. Our lab discovered one of the selectins, which is displayed on both endothelial cells and platelets, and also discovered its interacting partner, or ligand, on leukocytes. Examination of the molecular details of how selectins bind to their ligands has suggested means to inhibit these interactions in disease. We also collaborate with bioengineers to study how cellular and molecular features adjust to complex fluid dynamics to facilitate blood cell adhesion under flow. This work involves sophisticated video microscopy to visualize cell adhesion in flow chambers that mimic the conditions in the circulation.

Finally, my lab has generated a variety of genetically engineered mice in which key adhesion or signaling molecules have been deleted or modified. These mice provide powerful tools for investigating molecular function in models of inflammation or blood clotting in living animals.

Education
B.A., Yale University (cum laude), 1970
M.D., University of Chicago, 1974

Honors and Awards
1986-1991 NIH Research Career Development Award
1986 elected to American Society for Clinical Investigation
1993 Regents’ Award for Superior Accomplishment in Research and Creative Activity, University of Oklahoma
1994 elected to Association for American Physicians
1997 Investigator Recognition Award, International Society on Thrombosis and Haemostasis
1997 NIH Merit Award
1998 George Lynn Cross Research Professor, University of Oklahoma
2000 elected to Alpha Omega Alpha Honor Medical Society
2001 Fred Jones Distinguished Scientist, Oklahoma Medical Research Foundation
2001 elected Fellow of the American Heart Association
2008 Edward L. and Thelma Gaylord Prize for Scientific Achievement

Other Activities
Past or present service on editorial boards for Journal of Clinical Investigation, Blood, Arteriosclerosis, Thrombosis and Vascular Biology, Journal of Thrombosis and Hemostasis, and Journal of Biological Chemistry; reviewer for several other journals and publications; review committees and study sections for the National Institutes of Health, American Heart Association and other.

Joined OMRF Scientific Staff in 1987.

During responses to infection and tissue injury, circulating leukocytes and platelets adhere to each other and to the endothelial surface of blood vessels. Dysregulated adhesion of these cells contributes to thrombotic and inflammatory disorders. Leukocytes first tether to and then roll on vascular surfaces, a prerequisite for the subsequent arrest and then migration of the cells into the underlying tissues.

Tethering and rolling require rapid interaction of three related cell adhesion molecules called selectins with glycosylated cell-surface ligands. These interactions must withstand the forces applied to adherent cells by the wall shear stresses in the circulation. We discovered a sialomucin called PSGL-1, which is the major ligand on leukocytes for P-selectin and L-selectin and which also binds to E-selectin.

We have identified a number of molecular and cellular features that govern how selectins bind to their glycoconjugate ligands. These include the extension of binding domains above the cell surface, the clustering of selectins or their ligands through interactions of the cytosolic domains with clathrin-coated pits or the cytoskeleton and the dynamic extension and retraction of long, thin membrane tethers during rolling adhesion. We discovered that different levels of force affect the lifetimes of selectin-ligand bonds in a biphasic manner. Low forces prolong lifetimes (catch bonds), whereas higher forces shorten lifetimes (slip bonds). Catch bonds help explain the paradoxical requirement for a minimum flow rate to support cell adhesion mediated through L-selectin.

Studies with gene-targeted mice have a identified a novel role for PSGL-1 in mediating tethering of flowing leukocytes to E-selectin on inflamed vascular surfaces, a function for core 1-derived O-glycans in angiogenesis during development, and an unexpected contribution of cytokine receptors in bone marrow endothelial cells for hematopoiesis.

We are using biochemical and crystallographic approaches to further refine the structural features involved in selectin-ligand interactions, flow chambers to study the biophysical features required for selectins to support cell interactions under flow and a variety of gene-targeted mice to study the functions of selectins, PSGL-1, glycosyltransferases and cytokine receptors in vivo. Our long-term goal is to understand how lectin-carbohydrate interactions in the vasculature contribute to inflammation, hemostasis and hematopoiesis.

Recent Publications

Shao B, Yago T, Coghill PA, Klopocki AG, Mehta-D’Souza P, Schmidtke DW, Rodgers W, McEver RP. Signal-dependent slow leukocyte rolling does not require cytoskeletal anchorage of P-selectin glycoprotein ligand-1 (PSGL-1) or integrin alphaLbeta2. J Biol Chem 2012. [Abstract] EPub

Zarbock A, Ley K, McEver RP, Hidalgo A. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 2011. [Abstract] EPub

Sarangapani KK, Qian J, Chen W, Zarnitsyna VI, Mehta P, Yago T, McEver RP, Zhu C. Regulation of catch bonds by rate of force application. J Biol Chem 286:32749-32761, 2011. [Abstract]

Selected Publications

Miner JJ, Shao B, Wang Y, Chichili GR, Liu Z, Klopocki AG, Yago T, McDaniel JM, Rodgers W, Xia L, McEver RP. Cytoplasmic domain of P-selectin glycoprotein ligand-1 facilitates dimerization and export from the endoplasmic reticulum. J Biol Chem 286:9577-9586, 2011. [Abstract]

Shao B, Wahrenbrock MG, Yao L, David T, Coughlin SR, Xia L, Varki A, McEver RP. Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 118:4015-4023, 2011. [Abstract]

Liu Z, Miner JJ, Yago T, Yao L, Lupu F, Xia L, McEver RP. Differential regulation of human and murine P-selectin expression and function in vivo. J Exp Med 207:2975-2987, 2010. [Abstract]

Yago T, Shao B, Miner JJ, Yao L, Klopocki AG, Maeda K, Coggeshall KM, McEver RP. E-selectin engages PSGL-1 and CD44 through a common signaling pathway to induce integrin {alpha}L{beta}2-mediated slow leukocyte rolling. Blood 116:485-494, 2010. [Abstract]

Yago T, Fu J, McDaniel JM, Miner JJ, McEver RP, Xia L. Core 1-derived O-glycans are essential E-selectin ligands on neutrophils. Proc Natl Acad Sci U S A 107:9204-9209, 2010. [Abstract]

McEver RP. Rolling back neutrophil adhesion. Nat Immunol 11:282-284, 2010. [Abstract]