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-CSR-C (F1))
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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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