Vascular thiol isomerases modify disulfide bonds during thrombus formation in a manner analogous to how serine proteases cleave peptide bonds. Both thiol isomerases and serine proteases accumulate at sites of vascular injury and both are absolutely required for thrombus formation. Yet, while our knowledge of how serine proteases contribute to coagulation is deep, little is known about how thiol isomerases function in thrombosis. And while we have used our knowledge of coagulation factors to develop treatments for thrombotic disease, shortcomings of current antithrombotics in both efficacy and safety indicate a need to leverage new knowledge of alternative mediators of thrombus formation, such as thiol isomerases, for therapeutic benefit. We have identified novel inhibitors of protein disulfide isomerase (PDI) and have demonstrated their efficacy in pre-clinical models. We are currently conducting a phase II/III clinical trial testing the antithrombotic potential one of our PDI inhibitors in the setting of cancer. My research program will focus on the role of thiol isomerases in hemostasis and thrombosis with the objectives of determining the mechanisms by which thiol isomerases contribute to thrombus formation and identifying disease processes in which thiol isomerase-targeted therapies could be used therapeutically. Our studies will transform the field of thiol isomerases in hemostasis and thrombosis by the following advances: (a) a comprehensive understanding of how vascular thiol isomerases participate in thrombosis including how vascular thiol isomerases are regulated, the mechanism by which they act as redox sensors, and the identification of their substrates in thrombus formation, (b) conclusive evidence that thiol isomerases affect hemostasis and thrombosis differently, (c) the identification of coagulopathies and thrombotic diseases in which thiol isomerase-targeted therapies or diagnostics can be used, and (d) the introduction of thiol isomerase-targeted reagents in clinical practice. Over the next 7 years, we will evaluate the role of thiol isomerases in thrombosis associated with sepsis, inheritable hypercoagulable states, anti-phospholipid syndrome, and cancer. This program will thus address the fundamental biology of how thiol isomerases initiate thrombus formation and identify thrombotic diseases in which they participate.
We have shown that a group of enzymes called thiol isomerases promote blood clotting when released into the bloodstream. The current proposal focuses on understanding the mechanisms by which these thiol isomerases control clot formation and determining whether thiol isomerase inhibitors prevent lethal blood clots in patients. Successful completion of these studies will generate new diagnostic and therapeutic agents for diseases such as heart attacks, strokes, and venous clots.
|De Ceunynck, Karen; Peters, Christian G; Jain, Abhishek et al. (2018) PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury. Proc Natl Acad Sci U S A 115:E982-E991|
|Sharda, Anish; Flaumenhaft, Robert (2018) The life cycle of platelet granules. F1000Res 7:236|
|Jain, A; Barrile, R; van der Meer, A D et al. (2018) Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics. Clin Pharmacol Ther 103:332-340|
|Higgins, Sarah J; De Ceunynck, Karen; Kellum, John A et al. (2018) Tie2 protects the vasculature against thrombus formation in systemic inflammation. J Clin Invest 128:1471-1484|
|Flaumenhaft, Robert (2017) Advances in vascular thiol isomerase function. Curr Opin Hematol 24:439-445|
|Stopa, Jack D; Baker, Katherine M; Grover, Steven P et al. (2017) Kinetic-based trapping by intervening sequence variants of the active sites of protein-disulfide isomerase identifies platelet protein substrates. J Biol Chem 292:9063-9074|
|Flaumenhaft, Robert; De Ceunynck, Karen (2017) Targeting PAR1: Now What? Trends Pharmacol Sci 38:701-716|
|Stopa, Jack D; Neuberg, Donna; Puligandla, Maneka et al. (2017) Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight 2:e89373|
|Flaumenhaft, Robert (2017) Protease-Activated Receptor-1 Signaling: The Big Picture. Arterioscler Thromb Vasc Biol 37:1809-1811|