The Translational Research Center in Thrombotic and Hemostatic Disorders at Washington University is dedicated to understanding the role of proteases in the pathophysiology of thrombosis, which is a serious complication of many common diseases. This Center will pursue an interactive, multi-disciplinary approach involving 5 Projects and 4 Core Units that focus on microvascular and macrovascular thrombosis. Project 1 will characterize the molecular basis of ADAMTS13 substrate specificity, develop optimized assays to investigate the role of ADAMTS13 deficiency in thrombotic microangiopathy, and evaluate treatments to prevent relapses in thrombotic thrombocytopenic purpura. Project 2 will employ genomic sequencing to identify defects in complement regulation and hemostasis that cause thrombotic microangiopathy, including atypical hemolytic uremic syndrome, preeclampsia, and autoimmune disorders, and determine the biochemical mechanism by which these mutations cause disease. Project 3 will engineer an improved thrombin variant with exclusive activity toward protein C to optimize its anticoagulant and anti-inflammatory activity for treating thrombosis and sepsis. Project 4 will characterize new inhibitors of tissue factor and evaluate their efficacy in animal models of thrombosis, sepsis, HUS, and cancer progression. Project 5 will develop a first-in-class nanoparticle-based direct thrombin inhibitor with dual antiplatelet activity, and evaluate it for therapeutic dissolution and magnetic resonance imaging of thrombi. These projects rely on Core Units for logistics and oversight (Core A), patient enrollment and sample banking (Core C), and genomic analysis (Core D). New investigators will receive mentoring and training in translational and clinical research (Core B). The experimental approaches of the Center encompass basic molecular and state-of-the-art genetic methods, animal models, and biochemical and physiological studies of informative patients, as well as clinical studies to assess mechanism-based therapeutic approaches. These projects will facilitate the rapid translation of basic research discoveries into innovations in clinical care.

Public Health Relevance

The central goal of the TRC-THD at Washington University is to improve the health and survival of patients with thrombosis. This Center brings together basic scientists and clinical researchers to accelerate the translation of laboratory discoveries into new treatments for thrombosis, which is often a disabling or fatal event. (End of abstract)

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHL1)
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Link, Rebecca P
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Barranco-Medina, Sergio; Murphy, Mary; Pelc, Leslie et al. (2017) Rational Design of Protein C Activators. Sci Rep 7:44596
Shen, Guomin; Cui, Weidong; Zhang, Hao et al. (2017) Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer. Nat Struct Mol Biol 24:69-76
Chakraborty, Pradipta; Di Cera, Enrico (2017) Induced Fit Is a Special Case of Conformational Selection. Biochemistry 56:2853-2859
Sadler, J Evan (2017) Pathophysiology of thrombotic thrombocytopenic purpura. Blood 130:1181-1188
Liszewski, M Kathryn; Java, Anuja; Schramm, Elizabeth C et al. (2017) Complement Dysregulation and Disease: Insights from Contemporary Genetics. Annu Rev Pathol 12:25-52
Vedantham, Suresh; Goldhaber, Samuel Z; Julian, Jim A et al. (2017) Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis. N Engl J Med 377:2240-2252
Lokki, A Inkeri; Daly, Emma; Triebwasser, Michael et al. (2017) Protective Low-Frequency Variants for Preeclampsia in the Fms Related Tyrosine Kinase 1 Gene in the Finnish Population. Hypertension 70:365-371
Sanfilippo, K M; Wang, T F; Gage, B F et al. (2016) Incidence of venous thromboembolism in patients with non-Hodgkin lymphoma. Thromb Res 143:86-90
Wagner, Erin K; Raychaudhuri, Soumya; Villalonga, Mercedes B et al. (2016) Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD. Sci Rep 6:31531
Gillrie, Mark R; Renaux, Bernard; Russell-Goldman, Eleanor et al. (2016) Thrombin Cleavage of Plasmodium falciparum Erythrocyte Membrane Protein 1 Inhibits Cytoadherence. MBio 7:

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