A5015672238- Cell Adhesion Molecules Research
- Platelet Disorders and Treatments
- Protease and Inhibitor Mechanisms
- Immune Response and Inflammation
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Cellular Mechanics and Interactions
- Glycosylation and Glycoproteins Research
- Chemokine receptors and signaling
- Proteoglycans and glycosaminoglycans research
- S100 Proteins and Annexins
- Force Microscopy Techniques and Applications
- Lymphatic System and Diseases
- Biochemical and Structural Characterization
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Atherosclerosis and Cardiovascular Diseases
- Immunotherapy and Immune Responses
- Vector-borne infectious diseases
- Blood properties and coagulation
- T-cell and B-cell Immunology
- Autoimmune Bullous Skin Diseases
- Toxin Mechanisms and Immunotoxins
- Nausea and vomiting management
- Streptococcal Infections and Treatments
- Immune cells in cancer
Oklahoma Medical Research Foundation
2010-2020
University of Oklahoma Health Sciences Center
2001-2014
University of Minnesota
2008
Yale University
2003
University of Oklahoma
2002
Yokohama City University
1960-1999
Yokohama City University Hospital
1996
Kanagawa Cancer Center
1996
Kanagawa Prefectural Hospital Organization
1996
Arterial blood flow enhances glycoprotein Ibα (GPIbα) binding to vWF, which initiates platelet adhesion injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce requirement for adhesion. Here we show increasing force on GPIbα/vWF bonds first prolonged ("catch") and then shortened ("slip") bond lifetimes. Two vWD mutants, R1306Q R1450E, converted catch slip by prolonging lifetimes at low forces. Steered molecular dynamics simulations of GPIbα...
Selectin-ligand interactions mediate the tethering and rolling of circulating leukocytes on vascular surfaces during inflammation immune surveillance. To support rolling, these are thought to have rapid off-rates that increase slowly as wall shear stress increases. However, off-rate with force, an intuitive characteristic named slip bonds, is at odds a threshold requirement for selectin-mediated cell rolling. As drops below threshold, fewer cells roll those do less stably higher velocity. We...
P-selectin glycoprotein ligand-1 (PSGL-1) mediates rolling of leukocytes on under flow. The glycoproteins that enable leukocyte tethering to or E-selectin are not known. We used gene targeting prepare PSGL-1–deficient (PSGL-1–/–) mice, which were healthy but had moderately elevated total blood leukocytes. Fluid-phase bound approximately 70% fewer sites PSGL-1–/– than PSGL-1+/+ neutrophils. Compared with leukocytes, significantly rolled in vitro, because their initial was impaired. residual...
Flow-enhanced cell adhesion is an unexplained phenomenon that might result from a transport-dependent increase in on-rates or force-dependent decrease off-rates of adhesive bonds. L-selectin requires threshold shear to support leukocyte rolling on P-selectin glycoprotein ligand-1 (PSGL-1) and other vascular ligands. Low forces L-selectin–PSGL-1 (catch bonds), whereas higher (slip bonds). We determined dictated flow-enhanced L-selectin–bearing microspheres neutrophils PSGL-1. Catch bonds...
P-selectin glycoprotein ligand-1 (PSGL-1) mediates rolling of leukocytes on under flow. The glycoproteins that enable leukocyte tethering to or E-selectin are not known. We used gene targeting prepare PSGL-1–deficient (PSGL-1–/–) mice, which were healthy but had moderately elevated total blood leukocytes. Fluid-phase bound approximately 70% fewer sites PSGL-1–/– than PSGL-1+/+ neutrophils. Compared with leukocytes, significantly rolled in vitro, because their initial was impaired. residual...
Background— Ly-6C hi monocytes are key contributors to atherosclerosis in mice. However, the manner which selectively accumulate atherosclerotic lesions is largely unknown. Monocyte homing sites of primarily initiated by rolling on P- and E-selectin expressed endothelium. We hypothesize that P-selectin glycoprotein ligand-1 (PSGL-1), common ligand leukocytes, contributes preferential lesions. Methods Results— To test this hypothesis, we examined expression function PSGL-1 lo from wild-type...
Most platelet membrane proteins are modified by mucin-type core 1-derived glycans (O-glycans). However, the biological importance of O-glycans in clearance is unclear. Here, we generated mice with a hematopoietic cell-specific loss (HC C1galt1-/- ). These lack on platelets and exhibit reduced peripheral numbers. Platelets from HC show levels α-2,3-linked sialic acids increased accumulation liver relative to wild-type platelets. The preferential was lacking hepatic asialoglycoprotein receptor...
Leukocytes roll on selectins at nearly constant velocities over a wide range of wall shear stresses. Ligand-coupled microspheres faster and detach quickly as stress is increased. To examine whether the superior performance leukocytes reflects molecular features native ligands or cellular properties that favor selectin-mediated rolling, we coupled structurally defined selectin to K562 cells compared their rolling P-selectin. Microspheres bearing soluble P-selectin glycoprotein ligand...
L-selectin requires a threshold shear to enable leukocytes tether and roll on vascular surfaces. Transport mechanisms govern flow-enhanced tethering, whereas force governs rolling by prolonging the lifetimes of L-selectin–ligand complexes (catch bonds). Using selectin crystal structures, molecular dynamics simulations, site-directed mutagenesis, single-molecule kinetics experiments, Monte Carlo modeling, flow chamber adhesion studies, we show that eliminating hydrogen bond increase...
Leukocytes rolling on selectins extrude thin membrane tethers that might stabilize velocities despite marked alterations in wall shear stress. To test this hypothesis, we used differential interference contrast videomicroscopy to visualize formation and breakage of as neutrophils rolled P-selectin under flow. Neutrophils rapidly increased tether number stress rose decreased declined. Membrane invariably accompanied slower, more uniform steps translated into lower mean variances velocity....
Neutrophil recruitment, mediated by β2 integrins, combats pyogenic infections but also plays a key role in ischemia–reperfusion injury and other inflammatory disorders. Talin induces allosteric rearrangements integrins that increase affinity for ligands (activation). links to actin proteins enable formation of adhesions. Structural studies have identified talin1 mutant (L325R) perturbs activation without impairing talin’s capacity link proteins. Here, we found mice engineered express only...
Selectins mediate rolling of leukocytes by rapid formation and dissociation selectin–ligand bonds, which are assumed to require high mechanical strength prevent premature the forces applied in shear flow. This assumption is based largely on observation that increasing wall stress increases only modestly transient leukocyte tethers very low selectin densities. P-selectin binds N-terminal region glycoprotein ligand-1 (PSGL-1), a mucin leukocytes. Both PSGL-1 extended homodimers. We perfused...
Surface presentation of adhesion receptors influences cell adhesion, although the mechanisms underlying these effects are not well understood. We used a micropipette frequency assay to quantify how molecular orientation and length on membrane affected two-dimensional kinetic rates interactions with surface ligands. Interactions P-selectin, E-selectin, CD16A their respective ligands or antibody were demonstrate such effects. Randomizing receptor lowering its ligand- antibody-binding domain...
L-selectin expressed on leukocytes is involved in lymphocyte homing to secondary lymphoid organs and leukocyte recruitment into inflamed tissue. binds the sulfated sialyl Lewis x (6-sulfo-sLex) epitope present O-glycans of various glycoproteins high endothelial venules. In addition, interacts with dimeric mucin P-selectin glycoprotein ligand-1 (PSGL-1) leukocytes. PSGL-1 lacks 6-sulfo-sLex but contains tyrosine residues (Tyr-SO3)at positions 46, 48, 51 sLex a core 2-based O-glycan...
Leukocytes roll on P-selectin after its mobilization from secretory granules to the surfaces of platelets and endothelial cells. Tumor necrosis factor (TNF), IL-1β, lipopolysaccharide increase synthesis in murine but not human To explore physiological significance this difference gene regulation, we made transgenic mice bearing Selp crossed them with lacking (Selp−/−). The constitutively expressed platelets, cells, macrophages. mediated comparable neutrophil migration into inflamed...
Neutrophils roll on E-selectin in inflamed venules through interactions with cell-surface glycoconjugates. The identification of physiologic ligands neutrophils has been elusive. Current evidence suggests that P-selectin glycoprotein ligand-1 (PSGL-1), (ESL-1), and CD44 encompass all for E-selectin; ESL-1 use N-glycans to bind lacking core 2 O-glycans have partially defective E-selectin. These data imply PSGL-1 constitute ligands, neither glycan subset having a dominant role. enzyme...
Proteins involved in endocytosis promote the internalization and degradation of VEGFR3, ensuring valve formation lymphatic vessels.
Site-1 protease (S1P), encoded by MBTPS1, is a serine in the Golgi. S1P regulates lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis mice cultured cells. However, how differentially these diverse functions humans has been unclear. In addition, no human disease with deficiency identified. Here, we report pediatric patient an amorphic severely hypomorphic mutation MBTPS1. The unique combination of mutations results frequency functional MBTPS1 transcripts approximately...