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. Mutant plasminogen activators having specific domain deletions will also be constructed. Purity and structural integrity will be determined using site-specific monoclonal antibodies and standard biochemical methods. Of particular interest are the investigations to determine: (i) what precise molecular events result in activation of the catalytic subunit of ePA 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
Modified Research Career Development Award (K04)
Project #
1K04HL002414-01
Application #
3074480
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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