Plasminogen activator therapy for acute myocardial infarction has resulted in a significant improvement in mortality and morbidity in patients treated early after the onset of symptoms. Despite considerable interest in the development of new, more efficient plasminogen activators, none of those currently available can be administered without risk of hemorrhage. Any improvement that can be made to the specificity or sensitivity of these thrombolytic agents will, in all likelihood, be based on a complete understanding of the structural and functional features of naturally occurring plasminogen activators. The goal of the research proposed here is to gain a precise knowledge of the fibrin binding, inhibitory and catalytic activities of these natural activators. This will be accomplished by generating structurally and functionally intact A (fibrin binding) and B (catalytic) chains from tissue plasminogen activator (tPA) and single- chain urokinase-like plasminogen activator (scuPA), by both chemical and recombinant DNA methods, and then monoclonal antibodies. Of particular interest are the investigations to determine: (i) what precise molecular events result in activation of the catalytic subunit of tPA or scuPA in the presence of fibrin; (ii) the relative contribution of the A chains of tPA and scuPA (despite their structural homology) to fibrin binding, and (iii) whether it is possible to preserve the native function of the A and B chains of tPA and scuPA when fibrin affinity is imparted to them by an antifibrin monoclonal antibody.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL044307-01
Application #
3363044
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1989-07-01
Project End
1994-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Ruef, J; Kacharava, A; Pohl, J et al. (2000) Indications for the presence of an atypical protease-activated receptor on rat platelets. Ann Hematol 79:604-11
Bode, C; Hanson, S R; Schmedtje Jr, J F et al. (1997) Antithrombotic potency of hirudin is increased in nonhuman primates by fibrin targeting. Circulation 95:800-4
Wilcox, J N; Rodriguez, J; Subramanian, R et al. (1994) Characterization of thrombin receptor expression during vascular lesion formation. Circ Res 75:1029-38
Hayzer, D J; Cicila, G; Cockerham, C et al. (1994) Endothelin A and B receptors are down-regulated in the hearts of hypertensive rats. Am J Med Sci 307:222-7
Lubin, I M; Caban, R; Runge, M S (1993) The tissue plasminogen activator finger domain confers fibrin-dependent enhancement of catalytic activity to single-chain urokinase-type plasminogen activator. J Biol Chem 268:5550-6
Hayzer, D J; Brinson, E; Runge, M S (1992) A rat beta-interferon-induced mRNA: sequence characterization. Gene 117:277-8
Zhong, C Z; Hayzer, D J; Runge, M S (1992) Molecular cloning of a cDNA encoding a novel protein related to the neuronal vesicle protein synaptophysin. Biochim Biophys Acta 1129:235-8
Cockerham, C; Webb, M L; Hedberg, S A et al. (1991) Regulation of the rat aortic smooth muscle cell thromboxane A2 receptor. Trans Assoc Am Physicians 104:173-80