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)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL112303-03
Application #
8656767
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Link, Rebecca P
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wu, Xiaobin; Kim, Heejeong; Seravalli, Javier et al. (2016) Potassium and the K+/H+ Exchanger Kha1p Promote Binding of Copper to ApoFet3p Multi-copper Ferroxidase. J Biol Chem 291:9796-806
Pozzi, Nicola; Bystranowska, Dominika; Zuo, Xiaobing et al. (2016) Structural Architecture of Prothrombin in Solution Revealed by Single Molecule Spectroscopy. J Biol Chem 291:18107-16
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
Palekar, Rohun U; Vemuri, Chandu; Marsh, Jon N et al. (2016) Antithrombin nanoparticles inhibit stent thrombosis in ex vivo static and flow models. J Vasc Surg 64:1459-1467
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
Pozzi, Nicola; Chen, Zhiwei; Di Cera, Enrico (2016) How the Linker Connecting the Two Kringles Influences Activation and Conformational Plasticity of Prothrombin. J Biol Chem 291:6071-82
Gohara, David W; Di Cera, Enrico (2016) Molecular Mechanisms of Enzyme Activation by Monovalent Cations. J Biol Chem 291:20840-20848
Pozzi, Nicola; Zerbetto, Mirco; Acquasaliente, Laura et al. (2016) Loop Electrostatics Asymmetry Modulates the Preexisting Conformational Equilibrium in Thrombin. Biochemistry 55:3984-94
Pozzi, N; Di Cera, E (2016) Dual effect of histone H4 on prothrombin activation. J Thromb Haemost 14:1814-8
Eickhoff, Christopher S; Zhang, Xiuli; Vasconcelos, Jose R et al. (2016) Costimulatory Effects of an Immunodominant Parasite Antigen Paradoxically Prevent Induction of Optimal CD8 T Cell Protective Immunity. PLoS Pathog 12:e1005896

Showing the most recent 10 out of 71 publications