THROMBIN, SEPSIS AND MECHANISMS OF INFLAMMATION

University Of Illinois At Chicago, Chicago IL

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Abstract

DESCRIPTION (adapted from applicant's description): Thrombin cleaves both thrombin receptors (PAR-1 and PAR-3) in the extracellular amino-terminal extension and introduces the new amino- terminal region which acts as "ligand" for the receptor. The applicant has shown that the activation of PAR-1 in endothelial cell surface results in cell shape change, an increase in endothelial permeability and increased neutrophil sequestration on the endothelial cell surface. He proposes to determine (i) the mechanisms of thrombin- and inflammatory cytokine-induced DNA-protein binding sites in the PAR-1 and PAR-3 promoters (ii) the role of Galphai-dependent protein tyrosine kinase pathways in regulating the induction of transcription of PAR-1 and PAR-3 genes in endothelial cells (iii) the role of G protein-coupled receptor kinases on the agonist dependent desensitization of PAR-1 and PAR-3 in endothelial cells, and (iv) the roles of PAR-1 and PAR-3 in thrombin-mediated increases in pulmonary vascular permeabilitv using PAR-1 and PAR-3 knockout mouse models and the mechanism by which LPS and TNFa augment the thrombin-induced increase in vascular permeability.