Grant: Project Grant

Thrombosis is a condition that occurs as a result of unregulated blood clotting that blocks blood vessels and is a major cause of death and disability. Thrombosis can occur in various organs and can lead to heart attacks or stroke. Despite the availability of drugs that either prevent blood clotting or enhance 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 and 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. The objective of this project is to explore the biochemical and structural regulation of ADAMTS13 activity. We have engineered novel ADAMTS13 enzymes with increased stability in circulation that will be tested as novel therapies. Because ADAMTS13 is an important regulator of blood clotting, investigating the mechanisms that control its activity may lead to new therapies for thrombosis.