Plasminogen activator inhibitor-1 (PAI-1) and C1-inhibitor are serine proteinase inhibitors (serpins) present in plasma which control the activation of the fibrinolytic and intrinsic coagulation pathways respectively. PAI-1 excess is implicated as a risk factor for thrombosis, and C1-inhibitor deficiency causes angioedema. Serpins act by forming a stable complex with their target proteinase by mechanisms which are not clearly defined in detail. The focus of this project is to study the structurefunction relationships of these two serpins, with the aim of further elucidating the mechanism of serpin action, and identifying mechanisms for the regulation of serpin activity. Protein and peptide chemistry, and immunological techniques will be used to answer four main questions: a) what are the structural modifications observed on C1-inhibitor when it is cleaved at its reactive site, and how does this relate to inhibitory activity?; b) how is the partition ratio for the reaction of C1-inhibitor and PAI-1 with their target proteinases regulated by heparin and other ligands such as vitronectin?; c) which sites on C1-inhibitor and PAI-1 stabilize the interaction with their target proteinases, and can these interactions be used to design inhibitors of serpin function?;. and d) how does vitronectin stabilize the active form of PAI-1 and what are the binding sites on PAI-1 for vitronectin? This research will lead to a better understanding of the serpin mechanism, and the regulation of the proteolytic reactions of processes such as thrombus formation and lysis, as well as indicating possible targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL049242-06
Application #
2445236
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1993-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1999-06-30
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Dentistry
Type
Schools of Dentistry
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612