A5004105758- Platelet Disorders and Treatments
- Blood Coagulation and Thrombosis Mechanisms
- Cell Adhesion Molecules Research
- Venous Thromboembolism Diagnosis and Management
- Antiplatelet Therapy and Cardiovascular Diseases
- Atherosclerosis and Cardiovascular Diseases
- Blood properties and coagulation
- Immune Response and Inflammation
- Endoplasmic Reticulum Stress and Disease
- Systemic Lupus Erythematosus Research
- Angiogenesis and VEGF in Cancer
- Biochemical effects in animals
- Connexins and lens biology
- Biochemical and Structural Characterization
- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- Liver Disease Diagnosis and Treatment
- Lipoproteins and Cardiovascular Health
- Hemophilia Treatment and Research
- Glutathione Transferases and Polymorphisms
- Calpain Protease Function and Regulation
- Hormonal Regulation and Hypertension
- Plant biochemistry and biosynthesis
- Protease and Inhibitor Mechanisms
- Hormonal and reproductive studies
Harvard University
1999-2025
Beth Israel Deaconess Medical Center
2009-2025
Thrombosis Research Institute
2020
Institute of Molecular Biology and Biophysics
2016
Center for Vascular Biology Research
2005-2006
Versiti Blood Center of Wisconsin
2005
Medical College of Wisconsin
2005
University of Reading
2005
Scripps Research Institute
2004
Tufts University
1999
Using a laser-induced endothelial injury model, we examined thrombus formation in the microcirculation of wild-type and genetically altered mice by real-time vivo microscopy to analyze this complex physiologic process system that includes vessel wall, presence flowing blood, absence anticoagulants. We observe P-selectin expression, tissue factor accumulation, fibrin generation after platelet localization developing arterioles mice. However, lacking glycoprotein ligand 1 (PSGL-1) or...
P-selectin glycoprotein ligand 1 (PSGL-1) is a mucin-like selectin counterreceptor that binds to P-selectin, E-selectin, and L-selectin. To determine its physiological role in cell adhesion as mediator of leukocyte rolling migration during inflammation, we prepared mice genetically deficient PSGL-1 by targeted disruption the gene. The homozygous PSGL-1-deficient mouse was viable fertile. blood neutrophil count modestly elevated. There no evidence spontaneous development skin ulcerations or...
P-selectin glycoprotein ligand 1 (PSGL-1) is a sialomucin expressed on leukocytes that mediates neutrophil rolling the vascular endothelium. Here, role of PSGL-1 in mediating lymphocyte migration was studied using mice lacking PSGL-1. In contact hypersensitivity model, infiltration CD4(+) T lymphocytes into inflamed skin reduced PSGL-1-deficient mice. vitro-generated helper (Th)1 cells from did not bind to and migrated less efficiently than wild-type Th1 cells. To assess P- or...
Abstract Circulating tissue factor accumulates in the developing thrombus and contributes to fibrin clot formation. To determine whether derived from hematopoietic cells is delivered via factor-bearing microparticles or circulating leukocytes expressing on plasma membrane, we compared kinetics of accumulation arteriolar with time course leukocyte-thrombus interaction microparticle-thrombus microcirculation a living mouse using intravital high-speed widefield confocal microscopy. Tissue...
Protein disulfide isomerase (PDI), secreted by platelets and endothelial cells on vascular injury, is required for thrombus formation. Using PDI variants that form mixed complexes with their substrates, we identify kinetic trapping multiple substrate proteins, including vitronectin. Plasma vitronectin does not bind to αvβ3 or αIIbβ3 integrins platelets. The released reduces bonds plasma vitronectin, enabling αVβ3 αIIbβ3. In vivo studies of generation in mice demonstrate rapidly accumulates...
Both protein disulfide isomerase (PDI) and SARS-CoV-2 main protease (Mpro) are reliant on active site cysteines stabilized by adjacent amino acids. We reasoned that redox compounds might interfere with both enzymes acting in the vicinity of these reactive sites thus interfering viral replication thrombus formation. Our previous screen 1019 flavonoids identified several inhibit Mpro. goal was to identify phytochemical inhibitors Mpro block thiol isomerases antithrombotic. PDI, ERp57, ERp5,...
Plant-based flavonoids have been evaluated as inhibitors of β-coronavirus replication and therapies for COVID-19 on the basis their safety profile widespread availability. The SARS-CoV-2 main protease (Mpro) has implicated a target in silico. Yet no comprehensive vitro testing flavonoid activity against Mpro heretofore performed. We screened 1,019 diverse ability to inhibit Mpro. Multiple structure-activity relationships were identified among active compounds such enrichment galloylated...
Tissue factor (TF) is the primary initiator of blood coagulation in vivo and only for which a human genetic defect has not been described. As there are no routine clinical assays that capture contribution endogenous TF to initiation, extent reduced activity contributes unexplained bleeding unknown. Using whole genome sequencing, we identified heterozygous frameshift variant (p.Ser117HisfsTer10) F3, gene encoding TF, causing premature termination (TFshort) woman with bleeding. Routine...
Our understanding of hemorrhagic and thrombotic diseases has expanded with use models aimed at studying the vasculature using a variety different animals. Unlike in vitro experiments, these animal enable study broad continuum biological consequences induced by alterations made to single variable. This chapter briefly reviews used thrombosis research, focusing primarily on intravital fluorescence microscopy.
Lymphocyte homing to peripheral lymph nodes (LNs) requires L-selectin. Previous studies, however, suggest that there are L-selectin-independent mechanisms of lymphocyte homing. P-selectin glycoprotein ligand-1 (PSGL-1) is a major ligand for expressed in selectin-binding form on myeloid cells and subsets lymphoid cells. To discover whether PSGL-1 plays role homing, we examined leukocyte rolling adhesion the high endothelial venules (HEVs) subiliac LNs wild-type PSGL-1-deficient mice by...
Integrins function as bi-directional signaling transducers that regulate cell-cell and cell-matrix signals across the membrane. A key modulator of integrin activation is talin, a large cytoskeletal protein exists in an autoinhibited state quiescent cells. Talin 235-kDa composed N-terminal 45-kDa FERM (4.1, ezrin-, radixin-, moesin-related protein) domain, also known talin head series helical bundles rod domain. The domain consists four distinct lobes designated F0–F3. Integrin binding are...
Background In addition to its role on blood pressure, aldosterone (ALDO) also affects the hemostatic system leading increased experimental thrombosis. Striatin is an intermediate in rapid, nongenomic actions of ALDO. heterozygote knockout (