Molecular investigations of antithrombin instability and heparin binding mechanism

Funding Activity

Website
http://purl.org/au-research/grants/nhmrc/124301

Funding Status
Closed

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Funded Activity Summary

Thrombosis is a significant disease affecting a large number of people. The primary treatment for episodes of acute thrombosis is administration of the anticoagulant, heparin. The effector molecule through which heparin carries out its action is the serine proteinase inhibitor, antithrombin. This molecule regulates blood clotting by inhibiting the proteinases which carry out this process. Antithrombin is converted from a poor inhibitor of coagulation proteases to a very good inhibitor on binding heparin. This provides a control point for coagulation. The mechanism by which antithrombin is converted to a very good inhibitor of coagulation proteases involves a large change in the structure of this protein. These changes in structure are linked to the changes which occur when antithrombin becomes inactive through the process of polymerisation. Certain patients with thrombosis have been found to have changes in both the stability and heparin affinity of their antithrombin molecules, which forms the underlying basis for the disease. We wish to study the reasons for the effects of mutations in the antithrombin variants by making recombinant mutants which mimic the molecules in the thrombotic patients and carrying out detailed, sophisticated molecular analyses of their interaction with heparin and proteases and their stability under various conditions. Additionally we will engineer recombinant mutants of antithrombin which we believe will stabilise the molecule and potentially act as an improved supplement for therapy. This analysis will provide important insights into the functioning of both heparin and antithrombin and thereby significantly improve our understanding of the control of coagulation.

Funded Activity Details

Start Date: 01-01-2000

End Date: 01-01-2002

Funding Scheme: NHMRC Project Grants

Funding Amount: $195,691.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Oral and maxillofacial surgery

ANZSRC Socio-Economic Objective (SEO)

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Other Keywords

antithrombin | cardiovascular disease | heparin | latency | polymerization | regulation of coagulation/ blood clotting | thrombosis

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