Cellular initiation of the coagulation protease cascade participates in various biological responses including vascular diseases, athero-thrombotic lesions, immune and inflammatory reactions. Among cells implicated in the immune response, circulating blood monocytes efficiently initiate coagulation via surface expression of tissue factor and assembly of a proteolytic binary complex with factor VIIa. Monocytes also exhibits a broad range of molecular interactions with other cells, plasma, and extracellular matrix proteins. These mechanisms of cell:cell and cell:ligands communication are governed and modulated by a group of highly specialized surface receptors that include Mac-1 (CD 11b/CD18), LFA-1 (CD 11a/CD18), and p150,95 (CD 11c/CD18). These are leukocyte-restricted members of the superfamily of integrin adhesive receptors. Recent studies have shown that Mac-1, after appropriate signalling, can coordinate a molecular assembly of coagulation proteins fibrinogen and factor X. Because on monocytes this is followed by activation of X and rapid initiation of a procoagulant response, the hypothesis of an additional biological function of this receptor is postulated. The regions of Mac-1, fibrinogen and factor X implicated in this supramolecular interaction will be identified with synthetic peptides, monoclonal antibodies of defined recognition, limited proteolysis and ligand-receptor chemical cross-linking studies. The dynamic modulation of Mac-1 receptor function will be characterized in kinetic binding studies and early events of signal transduction in response to various agonists. Finally, the pathway of Mac- 1- activation of X will be characterized in the context of the monocyte- mediated process of fibrin formation. The overall project is designed to provide insights into a newly described function of Mac-1, inducible by physiologic agonists, that might collaboratively or alternatively contribute to the mechanism of fibrin deposition, in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043773-02
Application #
3362517
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1990-07-01
Project End
1992-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Craig, A; Fernandez-Reyes, D; Mesri, M et al. (2000) A functional analysis of a natural variant of intercellular adhesion molecule-1 (ICAM-1Kilifi). Hum Mol Genet 9:525-30
Altieri, D C (1999) Regulation of leukocyte-endothelium interaction by fibrinogen. Thromb Haemost 82:781-6
Mesri, M; Altieri, D C (1999) Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J Biol Chem 274:23111-8
Ambrosini, G; Adida, C; Sirugo, G et al. (1998) Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J Biol Chem 273:11177-82
Plescia, J; Conte, M S; VanMeter, G et al. (1998) Molecular identification of the cross-reacting epitope on alphaM beta2 integrin I domain recognized by anti-alphaIIb beta3 monoclonal antibody 7E3 and its involvement in leukocyte adherence. J Biol Chem 273:20372-7
Adida, C; Berrebi, D; Peuchmaur, M et al. (1998) Anti-apoptosis gene, survivin, and prognosis of neuroblastoma. Lancet 351:882-3
Papapetropoulos, A; Piccardoni, P; Cirino, G et al. (1998) Hypotension and inflammatory cytokine gene expression triggered by factor Xa-nitric oxide signaling. Proc Natl Acad Sci U S A 95:4738-42
Adida, C; Crotty, P L; McGrath, J et al. (1998) Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am J Pathol 152:43-9
Mesri, M; Plescia, J; Altieri, D C (1998) Dual regulation of ligand binding by CD11b I domain. Inhibition of intercellular adhesion and monocyte procoagulant activity by a factor X-derived peptide. J Biol Chem 273:744-8
Mesri, M; Altieri, D C (1998) Endothelial cell activation by leukocyte microparticles. J Immunol 161:4382-7

Showing the most recent 10 out of 39 publications