The long term goal of this project is to understand how adhesive interactions induce and integrate intercellular signaling between monocytes and neutrophils, which are leukocytes of the myeloid lineage, and endothelial cells. We also will determine how these interactions influence subsequent functional responses of the leukocytes in homeostatic inflammation and in inflammatory disease. The change in title of the project from """"""""Molecular Mechanisms of Neutrophil Adhesion to Endothelium"""""""" to """"""""Molecular Interactions of Myeloid Cells with Endothelium"""""""" reflects a larger scope, including a focus on adhesion-dependent signaling mechanisms and new investigations of the interactions of monocytes with endothelium, in addition to studies of PMNs. Specific adhesion molecules tether endothelial cells and myeloid cells together; similarly, such tethering molecules can bind platelets to myeloid cells and can mediate adhesion between the myeloid leukocytes themselves. We will determine how these adhesive interactions lead to the generation of intracellular signals that alter critical inflammatory functions of the myeloid cells. We will focus on expression of immediate-early genes, on cell spreading, and on related cellular responses. We will determine how molecules known to tether myeloid leukocytes transmit signals, and orchestrate them when acting in concert with other factors. Using isolated myeloid leukocytes and cultured endothelium, transfected cells, model membranes and purified molecules, we will characterize the roles of selectins, in Specific Aims l and 2.
In Specific Aim 3, we will use similar strategies to identify tethering and signaling mechanisms of ICAM-3, a new member of the ICAM family, in myeloid cell interactions.
In Specific Aim 4, we will examine """"""""outside-in"""""""" signaling by beta32 (CD11/CD18) integrins in myeloid cells using two traditional approaches, adhesion of leukocytes to specific ligands and incubation with antibodies that may induce functional alterations, and a novel approach - study of myeloid cells with targeted deletions of individual CD11/CD18 heterodimers. Information from these reduced systems will then be used to analyze complex models of inflammation (cell-cell interactions in vitro) and, ultimately, to identify new strategies for understanding and modifying inflammatory events in vivo and in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044525-12
Application #
6389127
Study Section
Pathology A Study Section (PTHA)
Program Officer
Massicot-Fisher, Judith
Project Start
1990-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
12
Fiscal Year
2001
Total Cost
$300,721
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Rondina, M T; Freitag, M; Pluthero, F G et al. (2016) Non-genomic activities of retinoic acid receptor alpha control actin cytoskeletal events in human platelets. J Thromb Haemost 14:1082-94
Hottz, Eugenio D; Lopes, Juliana F; Freitas, Carla et al. (2013) Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood 122:3405-14
Hottz, E D; Oliveira, M F; Nunes, P C G et al. (2013) Dengue induces platelet activation, mitochondrial dysfunction and cell death through mechanisms that involve DC-SIGN and caspases. J Thromb Haemost 11:951-62
Kraemer, Bjoern F; Campbell, Robert A; Schwertz, Hansjörg et al. (2012) Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets. Blood 120:5014-20
Vieira-de-Abreu, Adriana; Campbell, Robert A; Weyrich, Andrew S et al. (2012) Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 34:5-30
Rondina, M T; Schwertz, H; Harris, E S et al. (2011) The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost 9:748-58
Rowley, Jesse W; Oler, Andrew J; Tolley, Neal D et al. (2011) Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood 118:e101-11
Kraemer, Bjoern F; Campbell, Robert A; Schwertz, Hansjorg et al. (2011) Novel anti-bacterial activities of ýý-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog 7:e1002355
Schwertz, Hansjorg; Koster, Sarah; Kahr, Walter H A et al. (2010) Anucleate platelets generate progeny. Blood 115:3801-9
Yost, Christian C; Weyrich, Andrew S; Zimmerman, Guy A (2010) The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie 92:692-7

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