This application for a Translational Research Center in Thrombotic and Hemostatic Disorders describes research to develop a novel class of antithrombotic agents. Component projects explore protein disulfide isomerase (PDl) as an antithrombotic target using isoquercetin, quercetin 3-rutinoside and quercetin as inhibitors of PDl. In Project #1, Dr. Bruce Furie, with Dr. Barbara Furie and Dr. Mingdong Huang, explore the mechanism by which PDl participates in thrombus generation and will test in vivo thrombosis models whether PDl inhibitor can prevent thrombosis in mice. Dr. Huang will solve the crystal structure of PDl with and without a bound PDl inhibitor. In Project #2, Dr. Robert Flaumenhaft and Dr. Natalia Beglova will search for more potent PDl inhibitors at the Broad Institute. PDl domains will be expressed and their interaction with small molecule PDl inhibitors examined by NMR spectroscopy. New ligands will be designed, synthesized by chemists at the Broad Institute and subsequently tested. This project will expand the number of PDl ligands available for evaluation in this new class of antithrombotics. In Project #3, Dr. Jeffrey Zwicker, with Dr. Donna Neuberg, will explore the antithrombotic properties of quercetin and isoquercetin in humans, agents approved for human use. A pharmacokinetic study with quercetin and isoquercetin in the presence and absence of ascorbic acid will be performed to determine optimal delivery. The effectiveness of the PDl inhibitor in three separate human studies will be evaluated: thromboembolic events in patients with cancer;heparin-induced thrombocytopenia and thrombosis;anti-phospholipid syndrome. This TRC-THD will include four cores that will provide support to the overall program. The Administrative Core (Core A) will be directed by Dr. Bruce Furie, and will coordinate the activities of the three projects. The Intravital Microscopy and Animal Core (Core B) will be directed by Dr. Barbara C. Furie. The Molecular and Structural Biology core (Core C) will be co-directed by Dr. Mingdong Huang and Dr. Natalia Beglova. The Translational Skills Development Core (Core D) will be directed by Dr. Kenneth Bauer. The Center will work to develop a new class of antithrombotic agents directed against PDl with both antiplatelet and anticoagulant properties.

Public Health Relevance

Arterial thrombosis resulting in myocardial infarction and stroke as well as venous thromboembolism resulting in deep vein thrombosis and pulmonary embolism remain the most common causes of mortality in the United States. There is a need to develop new classes of antithrombotic therapies with both antiplatelet and anticoagulant activity. Studies in this project will determine whether PDl is a novel target for antithrombotic therapy. (End of Abstract)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54HL112302-01
Application #
8250091
Study Section
Special Emphasis Panel (ZHL1-CSR-C (F1))
Program Officer
Link, Rebecca P
Project Start
2012-09-01
Project End
2017-04-30
Budget Start
2012-09-01
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$2,264,159
Indirect Cost
$955,255
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Stopa, Jack D; Zwicker, Jeffrey I (2018) The intersection of protein disulfide isomerase and cancer associated thrombosis. Thromb Res 164 Suppl 1:S130-S135
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
Bowley, Sheryl R; Fang, Chao; Merrill-Skoloff, Glenn et al. (2017) Protein disulfide isomerase secretion following vascular injury initiates a regulatory pathway for thrombus formation. Nat Commun 8:14151
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, R (2016) Probing for thiol isomerase activity in thrombi. J Thromb Haemost 14:1067-9
Galinski, Christine N; Zwicker, Jeffrey I; Kennedy, Daniel R (2016) Revisiting the mechanistic basis of the French Paradox: Red wine inhibits the activity of protein disulfide isomerase in vitro. Thromb Res 137:169-73
Schulman, Sol; Bendapudi, Pavan; Sharda, Anish et al. (2016) Extracellular Thiol Isomerases and Their Role in Thrombus Formation. Antioxid Redox Signal 24:1-15
Flaumenhaft, Robert; Furie, Bruce (2016) Vascular thiol isomerases. Blood 128:893-901

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