Grant: Operating Grant

Rapid blood clot formation at sites of injury is critical to stop blood loss. Deregulation of blood clotting can lead to thrombosis; the formation of clots that block blood vessels and are the root cause of life-threatening disorders, such as heart attacks and strokes. There is mounting evidence that (a) factor XII, a blood clotting protein, is the initiator of life-threatening thrombosis, and (b) substances released from damaged cells , such as DNA and RNA, can activate factor XII and trigger clotting. It is not known how factor XII is regulated. We have evidence that HRG, a protein that circulates in the blood, modulates clotting by binding DNA and RNA and preventing them from activating factor XII and by binding factor XII and decreasing its activity. In support of its role as a regulator, we have shown that mice lacking HRG have accelerated clotting; a response that is reversed when they are given HRG. The purpose of this application is to better define how HRG regulates clotting and to use this information to develop new treatments to prevent thrombosis.