Thrombin(s) has become among the best studied serine proteinases and has both enzymic (proteolytic) and nonenzymic (hormonal) bioregulatory functions in hemostasis, wound healing, and related physiologic processes. Some 10- to 20- million units of human Alpha-thrombin with high clotting and all other thrombin-ascribed activities continue to be produced in our laboratory annually for our own studies, as well as for those in other laboratories (U.S. and abroad). In addition to this form, we are making enzymically active forms lacking clotting activity (e.g., by autolytic, tryptic, elastolytic digestion) and enzymically inactivated forms posessing hormonal activities (e.g., by modification with i-Pr2P-F, D-Phe-Pro-Arg-Ch2-Cl) in order to map active-site regions and structural domains of thrombin required for enzymic and nonenzymic functions. We are also attempting to isolate hormonally active fragments (e.g., leucocyte proteinase digests), which might participate in post clotting events. Collaborative studies provide us with the ability to assess various biological activities (e.g., platelet responses, vascular endothelial monolayer permeability, leucocyte functions). Other collaborative studies will also include the evaluation of human (pro)thrombin recombinant gene products. Our extended laboratory approach is believed to have resulted in major contributions (e.g., the majority of materials for the recent Satellite Symposium of the Xth Congress of the ISTH on """"""""Cellular Events Mediated by Thrombin and Related Proteinases"""""""" (San Diego, July 1985) and the New York Academy of Sciences Conference on """"""""Bioregulatory Functions of Thrombin"""""""" (New York, February 5-7, 1986).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL013160-19
Application #
3334574
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1978-07-01
Project End
1994-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
19
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
110521739
City
Menands
State
NY
Country
United States
Zip Code
12204
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Witting, J I; Brezniak, D V; Andersen, T T et al. (1997) Thrombin affinity mapping of its receptor tethered ligand. Blood Coagul Fibrinolysis 8:65-9
Johnson, P C; Heil, B V; Parva, B et al. (1996) Thrombin activity on dissected and anastomosed human arteries. J Surg Res 60:193-8
Armstrong, M T; Fenton 2nd, J W; Andersen, T T et al. (1996) Thrombin stimulation of matrix fibronectin. J Cell Physiol 166:112-20
Schini-Kerth, V B; Fisslthaler, B; Andersen, T T et al. (1995) Thrombin prevents the expression of inducible nitric oxide synthase in vascular smooth muscle cells by a proteolytically-activated thrombin receptor. Thromb Haemost 74:980-6
Seiler, S M; Peluso, M; Michel, I M et al. (1995) Inhibition of thrombin and SFLLR-peptide stimulation of platelet aggregation, phospholipase A2 and Na+/H+ exchange by a thrombin receptor antagonist. Biochem Pharmacol 49:519-28
Gralnick, H R; Williams, S; McKeown, L P et al. (1994) High-affinity alpha-thrombin binding to platelet glycoprotein Ib alpha: identification of two binding domains. Proc Natl Acad Sci U S A 91:6334-8
Salatti, J A; Fenton 2nd, J; Anton, P et al. (1994) alpha-thrombin bound to extracellular endothelial matrix induces pronounced fibrin deposition and platelet thrombus growth in flowing non-anticoagulated human blood. Blood Coagul Fibrinolysis 5:561-6
Beecher, K L; Andersen, T T; Fenton 2nd, J W et al. (1994) Thrombin receptor peptides induce shape change in neonatal murine astrocytes in culture. J Neurosci Res 37:108-15
Smirnova, I V; Ho, G J; Fenton 2nd, J W et al. (1994) Extravascular proteolysis and the nervous system: serine protease/serpin balance. Semin Thromb Hemost 20:426-32

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