The goal of this program is to define molecular mechanisms which contribute to thrombus formation and dissolution. Information gained from these studies will be used to develop strategies for controlling thrombosis in vivo and designing tests for monitoring thrombotic events. Dr. David Loskutoff will study the structure, function and cellular biology of proteins that specifically bind to plasminogen activator inhibitor-1, and the importance of this process. The mechanisms by which theses proteins stabilize plasminogen activator-1 and the importance of this process in the regulation of fibrinolysis will be explored. Dr. Mark Ginsberg will define changes induced in the glycoprotein IIb/IIIa receptor of platelets following occupation by arg-gly-asp bearing ligands. This work will extend observations made with PMI-1, an antibody which recognizes a neo-antigenic site expressed on the occupied glycoprotein IIb/IIIa complex. Dr. Zaverio Ruggeri will define the structure and functional relationship of the von Willebrand Factor domains mediating binding of this molecule to collagen and heparin. Structural differences between von Willebrand Factor, fibrinogen and fibronectin which govern specificity of binding to adhesion receptors will be defined and development of peptides which block these interactions will be continued. Dr. Stephen Hanson will evaluate the effect of blocking ligand-platelet interactions on thrombosis in non-human primate models. Antibodies and peptides which selectively block different glycoprotein IIb/IIIa ligands as well as agents blocking von Willebrand Factor binding to glycoprotein Ib will be studied. Dr. John Griffin will study the two major plasma inhibitors of protein C, identify protein structural regions responsible for the interaction of activated protein C with these inhibitors, develop nw methods to characterize complexes of activated protein C with these inhibitors in blood and plasma, and will seek to identify variant protein C alleles. Dr. Laurence Harker will use activated protein C, synthetic inhibitors of thrombin, and hirudin to extend preliminary studies which indicate that thrombin is generally important in the formation of thrombus under either high or low shear flow conditions in vivo. Dr. Theodore Zimmerman will use antibodies with defined epitopes as probes of Factor VIII structure-function relationships. The results of antibody studies will be used in the design of mutant Factor VIII molecules to identify structures which mediate the different functions of Factor VIII.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL031950-06
Application #
3098229
Study Section
Heart, Lung, and Blood Research Review Committee B (HLBB)
Project Start
1984-04-01
Project End
1994-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037
Klann, Jane E; Kim, Stephanie H; Remedios, Kelly A et al. (2018) Integrin Activation Controls Regulatory T Cell-Mediated Peripheral Tolerance. J Immunol 200:4012-4023
Griffin, John H; Zlokovic, Berislav V; Mosnier, Laurent O (2018) Activated protein C, protease activated receptor 1, and neuroprotection. Blood 132:159-169
Sinha, Ranjeet K; Wang, Yaoming; Zhao, Zhen et al. (2018) PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke. Blood 131:1163-1171
Xu, Xiaohong Ruby; Wang, Yiming; Adili, Reheman et al. (2018) Apolipoprotein A-IV binds ?IIb?3 integrin and inhibits thrombosis. Nat Commun 9:3608
Gupta, Naveen; Liu, Roland; Shin, Stephanie et al. (2018) SCH79797 improves outcomes in experimental bacterial pneumonia by boosting neutrophil killing and direct antibiotic activity. J Antimicrob Chemother 73:1586-1594
Gupta, Naveen; Sinha, Ranjeet; Krasnodembskaya, Anna et al. (2018) The TLR4-PAR1 Axis Regulates Bone Marrow Mesenchymal Stromal Cell Survival and Therapeutic Capacity in Experimental Bacterial Pneumonia. Stem Cells 36:796-806
Amar, Arun Paul; Sagare, Abhay P; Zhao, Zhen et al. (2018) Can adjunctive therapies augment the efficacy of endovascular thrombolysis? A potential role for activated protein C. Neuropharmacology 134:293-301
Kamikubo, Yuichi; Mendolicchio, G Loredana; Zampolli, Antonella et al. (2017) Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex. Blood 130:1661-1670
Rothmeier, Andrea S; Marchese, Patrizia; Langer, Florian et al. (2017) Tissue Factor Prothrombotic Activity Is Regulated by Integrin-arf6 Trafficking. Arterioscler Thromb Vasc Biol 37:1323-1331
Subramaniam, Saravanan; Jurk, Kerstin; Hobohm, Lukas et al. (2017) Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development. Blood 129:2291-2302

Showing the most recent 10 out of 428 publications