The overall objective of the Duke Translational Medicine Institute Center for Thrombotic and Hemostatic Disorders (DTMI-CTHD) is to establish a home for and provide support for investigators focused upon developing novel approaches to treat thrombotic and hemostatic diseases at Duke University. As its name indicates, the DTMI-CTHD will be tightly integrated with the CTSA supported Duke Translational Medicine Institute, which is the home for all translational and clinical research at Duke. The scientific focus of the DTMI-CTHD is on treating thrombotic disease in acute care prothrombotic settings. Profound antithrombotic therapy is critical during both percutaneous and surgical revascularization procedures to prevent deleterious effects of coagulation and platelet aggregation triggered by foreign materials and vascular trauma. Such potent antithrombotic therapy is associated with the common complication of bleeding which makes management of such therapy challenging. To address this challenge, we have established a translational research program that has three research projects and three cores. Each project and core is led by a seasoned investigator(s). Project 1 will evaluate potent, yet antidote controllable combinations of antithrombotic agents in cell and animal based models. Project 2 will translate the first antidote controllable antiplatelet agent, a RNA aptamer against von Willebrand factor (VWF) and its matched antidote oligonucleotide, into phase 1a and 1b studies. Project 3 will employ clinical samples to develop unique laboratory profiles that can be applied to various clinical settings to predict the safety and efficacy of targeted antithrombotic therapy. Collectively these projects will result in 1.) a more thorough basic mechanistic understanding of the prothrombotic environment engendered during common revascularization procedures, 2.) translation of a novel approach to control platelet activity into a phase 1 clinical trial to begin to address a major challenge of antithrombotic therapy, bleeding and 3.) methods to identify and manage the optimal antithrombotic therapy for treatment of individual patients. The molecular, educational and administrative cores will support each of these projects as well as facilitate basic, translational and clinical research on thrombotic and hemostatic disorders across the Duke campus. Each project and core will be briefly discussed below along with the overall research environment at Duke.

Public Health Relevance

We believe that the proposed projects will allow us to identify the approach and agent(s) that result in the highest net therapeutic benefit to limit thrombosis and monitor antithrombotic therapy in a variety of clinically relevant models, and to validate these observations using samples obtained from patients participating in a first-in-human phase 1 clinical trial.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL112307-04
Application #
8840627
Study Section
Special Emphasis Panel (ZHL1-CSR-C (F1))
Program Officer
Kindzelski, Andrei L
Project Start
2012-05-15
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
4
Fiscal Year
2015
Total Cost
$2,213,927
Indirect Cost
$803,514
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Fager, A M; Machlus, K R; Ezban, M et al. (2018) Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity. J Thromb Haemost 16:1817-1829
Lee, Jaewoo; Lee, Youngju; Xu, Li et al. (2017) Differential Induction of Immunogenic Cell Death and Interferon Expression in Cancer Cells by Structured ssRNAs. Mol Ther 25:1295-1305
Lee, Jaewoo; Jackman, Jennifer G; Kwun, Jean et al. (2017) Nucleic acid scavenging microfiber mesh inhibits trauma-induced inflammation and thrombosis. Biomaterials 120:94-102
Hoffman, Maureane; Monroe, Dougald M (2017) Impact of Non-Vitamin K Antagonist Oral Anticoagulants From a Basic Science Perspective. Arterioscler Thromb Vasc Biol 37:1812-1818
Nimjee, Shahid M; White, Rebekah R; Becker, Richard C et al. (2017) Aptamers as Therapeutics. Annu Rev Pharmacol Toxicol 57:61-79
Lee, Youngju; Urban, Johannes H; Xu, Li et al. (2016) 2'Fluoro Modification Differentially Modulates the Ability of RNAs to Activate Pattern Recognition Receptors. Nucleic Acid Ther 26:173-82
Soule, Erin E; Bompiani, Kristin M; Woodruff, Rebecca S et al. (2016) Targeting Two Coagulation Cascade Proteases with a Bivalent Aptamer Yields a Potent and Antidote-Controllable Anticoagulant. Nucleic Acid Ther 26:1-9
Ganson, Nancy J; Povsic, Thomas J; Sullenger, Bruce A et al. (2016) Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer. J Allergy Clin Immunol 137:1610-1613.e7
Woodruff, Rebecca S; Sullenger, Bruce A (2015) Modulation of the Coagulation Cascade Using Aptamers. Arterioscler Thromb Vasc Biol 35:2083-91
Bompiani, Kristin M; Lohrmann, Jens L; Pitoc, George A et al. (2014) Probing the coagulation pathway with aptamers identifies combinations that synergistically inhibit blood clot formation. Chem Biol 21:935-44