Haematology Research

Lab head: Freda Janet Passam
Location: Heart Reserach Institute Labs, Level 3 East, Charles Perkins Centre

Thiol isomerases as novel antithrombotic targets

Primary supervisor: Freda Passam

Aim:To discover alternative pathways in the clotting system that can be targeted to develop efficient and safer antithrombotic drugs.

Background:An exciting recent discovery in the thrombosis field is that thiol isomerases form a new clotting pathway. Thiol isomerases are a group of enzymes that regulate the function of blood cell receptors and clotting proteins by reacting with their disulphide bonds. We have identified a thiol isomerase, named ERp5, which is released into the circulation from activated platelets and promotes clot formation in vivo.                                                                                                                                                                                                                         

Project overview:In this project we will dissect the role of ERp5 in platelet function and clot formation by using mice with genetic deletion of ERp5 in their platelets. We will investigate how this thiol isomerase regulates the interaction of platelets with clotting proteins (fibrinogen, von Willebrand factor) and vascular cells (endothelial cells and neutrophils). We will explore the potential of ERp5 inhibitors to prevent thrombus formation and become candidate antithrombotic drugs.

Techniques:These studies will employ platelet function tests, cell perfusion assays, flow cytometry and confocal microscopy. This project will provide the opportunity to learn the method of intravital microscopy for the study of clot formation in mice.

Relevant publications:

1. Sharda A, Furie B. Regulatory role of thiol isomerases in thrombus formation. Expert Rev Hematol. 2018;11(5):437-448.

2. Passam FH, Lin L, Gopal S, Stopa JD, Bellido-Martin L, Huang M, Furie BC, Furie B. Both platelet- and endothelial cell-derived ERp5 support thrombus formation in a laser-induced mouse model of thrombosis. Blood. 2015;125(14):2276-2285.

3. Jasuja R, Passam FH, Kennedy DR, Kim SH, van Hessem L, Lin L, Bowley SR, Joshi SS, Dilks JR, Furie B, Furie BC, Flaumenhaft R. Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents. J Clin Invest. 2012;122(6):2104-2113.

Discipline: Pathology
Keywords: Coagulation and platelets, Haematology, Thrombosis