Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM058531-01
Application #
2729075
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1999-02-01
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612

  Publications

Sundivakkam, Premanand C; Natarajan, Viswanathan; Malik, Asrar B et al. (2013) Store-operated Ca2+ entry (SOCE) induced by protease-activated receptor-1 mediates STIM1 protein phosphorylation to inhibit SOCE in endothelial cells through AMP-activated protein kinase and p38? mitogen-activated protein kinase. J Biol Chem 288:17030-41
Sundivakkam, Premanand C; Freichel, Marc; Singh, Vandana et al. (2012) The Ca(2+) sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated Ca(2+) entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells. Mol Pharmacol 81:510-26
Thippegowda, Prabhakar B; Singh, Vandana; Sundivakkam, Premanand C et al. (2010) Ca2+ influx via TRPC channels induces NF-kappaB-dependent A20 expression to prevent thrombin-induced apoptosis in endothelial cells. Am J Physiol Cell Physiol 298:C656-64
Minshall, Richard D; Vandenbroucke, Emily E; Holinstat, Michael et al. (2010) Role of protein kinase Czeta in thrombin-induced RhoA activation and inter-endothelial gap formation of human dermal microvessel endothelial cell monolayers. Microvasc Res 80:240-9
Bair, Angela M; Thippegowda, Prabhakar B; Freichel, Marc et al. (2009) Ca2+ entry via TRPC channels is necessary for thrombin-induced NF-kappaB activation in endothelial cells through AMP-activated protein kinase and protein kinase Cdelta. J Biol Chem 284:563-74
Sundivakkam, Premanand C; Kwiatek, Angela M; Sharma, Tiffany T et al. (2009) Caveolin-1 scaffold domain interacts with TRPC1 and IP3R3 to regulate Ca2+ store release-induced Ca2+ entry in endothelial cells. Am J Physiol Cell Physiol 296:C403-13
Xue, Jiaping; Thippegowda, Prabhakar B; Hu, Guochang et al. (2009) NF-kappaB regulates thrombin-induced ICAM-1 gene expression in cooperation with NFAT by binding to the intronic NF-kappaB site in the ICAM-1 gene. Physiol Genomics 38:42-53
Tiruppathi, Chinnaswamy; Shimizu, Jun; Miyawaki-Shimizu, Kayo et al. (2008) Role of NF-kappaB-dependent caveolin-1 expression in the mechanism of increased endothelial permeability induced by lipopolysaccharide. J Biol Chem 283:4210-8
Kwiatek, Angela M; Minshall, Richard D; Cool, David R et al. (2006) Caveolin-1 regulates store-operated Ca2+ influx by binding of its scaffolding domain to transient receptor potential channel-1 in endothelial cells. Mol Pharmacol 70:1174-83
Tiruppathi, Chinnaswamy; Ahmmed, Gias U; Vogel, Stephen M et al. (2006) Ca2+ signaling, TRP channels, and endothelial permeability. Microcirculation 13:693-708

Showing the most recent 10 out of 24 publications