Grant: Project Grant

Thrombosis is a pathological condition that occurs as a result of unregulated blood clotting that occludes blood vessels, and is a major cause of morbidity and mortality. Thrombosis can manifest in various organs and can lead to heart attacks or stroke. Despite the availability of drugs that either prevent blood clotting or encourage clot breakdown, thrombosis is responsible for 1 in 4 deaths in Canada and worldwide. Current therapies are limited by the need to balance their effectiveness at treating thrombosis with their risk of causing bleeding. As a result, more research is needed to explore the mechanisms of thrombosis in order to identify new targets for safe and effective therapy. A critical step in the progression to thrombosis is the recruitment of platelets to the injured blood vessel. This is accomplished in part by the protein Von Willebrand Factor (VWF). VWF is a long string-like protein that adheres to the site of vessel injury and captures platelets flowing in blood. Recruitment of too many platelets can lead to thrombosis. ADAMTS13 is a protease that cuts VWF strings, shortening them and reducing their platelet-capturing activity. Changes in ADAMTS13 activity can lead to dysfunctional VWF and cause either bleeding or thrombosis. However, there is currently very little that is known about the regulation of ADAMTS13. ADAMTS13 is known to remain in a folded compact form in circulation that becomes extended when it interacts with and cuts VWF. Whether this folded form of ADAMTS13 contributes to the regulation of its protease activity is currently not known. Therefore, the objective of this project is to explore the biochemical and structural mechanisms that contribute to the regulation of ADAMTS13. Because ADAMTS13 is an important regulator of blood clotting, investigating the mechanisms that control its activity may reveal novel targets for antithrombotic therapy development.