Grant: Project Grant

Platelets are small blood cells that help control bleeding. Our team is studying an inherited disorder called Quebec platelet disorder (QPD) that alters platelets and causes serious bleeding. Our team has made important discoveries about QPD including its genetic cause. In Canada, about 1:200,000 Quebecers has QPD and each person with QPD has a 50:50 chance of passing on QPD each of their children. QPD causes bleeding because it increases a clot busting enzyme called urokinase plasminogen activator (uPA). Persons with QPD have very high levels of uPA in platelets but not in other cells - we are trying to find out why. QPD is caused by a "duplication mutation" which means that a person with QPD an extra copy of the uPA gene and nearby DNA. In QPD cells that make platelets, uPA production is >100 times normal, which is far more than expected for having one extra uPA gene. Additionally, the overproduction of uPA occurs only in QPD cells that make platelets. We explored why and found that QPD duplicates a gene enhancer ("turn on switch") for vinculin (the next gene) - this switch is active only in cells that make platelets. QPD puts the extra copy of this switch right front of the uPA gene. We suspect this is why the gene for uPA becomes turned on too much in QPD cells that make platelets. We will use special methods, including "chromatic conformation capture methods" to test this "swtich" and if it is the reason that the uPA gene in is switched on in QPD cells that make platelets. We will also use special methods to alter genes to test if we can correct the problem in QPD cells that make platelets. Our team has made important discoveries about QPD. We have exciting new information and the technical skills that are needed to study what causes QPD. The study will give us important new information on how genes are controlled when the body makes platelets and how this is changed by QPD. The study will give us new insights on what causes platelet disorders