This application seeks to improve basic understanding of molecular mechanisms that mediate cytoprotective actions of coagulation proteases on cells. Available therapeutic solutions for vascular, thrombotic, and inflammatory diseases are limited and mortality rates remain unacceptably high. Beneficial effects of activated protein C (APC) on cells contrast with proinflammatory effects of other coagulation proteases (e.g. thrombin and factor Xa) on cells and initiated novel perspectives on the intricate complex networks of receptor-mediated cross talk in cells. Improving therapeutic success requires a more thorough understanding of the molecular mechanisms involved. This proposal is centered on the endothelial protein C receptor (EPCR), a key cytoprotective receptor. The long-term objectives of this application are to contribute to diagnostic and therapeutic progress for vascular, thrombotic, and inflammatory diseases by advancing knowledge through both basic and translational research. The goal of this application is to gain novel insights into the molecular mechanisms of cytoprotective actions mediated by EPCR. The major focus of this application is on structure- function relationships for EPCR that underlie EPCR's cofactor role in the transduction of clinically relevant APC-mediated cytoprotective effects and on translation of this information into improved therapeutic strategies for thrombotic inflammatory diseases. Novel hypotheses will be tested using biochemical and cellular biology methods.
The specific aims are: 1) To generate engineered EPCR variants with unique properties that will enhance its ability to mediate cytoprotective effects, 2) To characterize the structure-function determinants for EPCR-dependent PAR-1 activation that are responsible for APC-mediated cytoprotective effects on cells, and 3) To define the thrombotic complications associated with """"""""off-target"""""""" Heparin-Induced Thrombocytopenia (HIT) antibodies against PF4-EPCR and PF4-thrombomodulin (TM) complexes. Succesfull completion of the proposed studies will increase our knowledge and understanding of vascular, thrombotic, and inflammatory diseases and may provide a platform for the development of novel therapeutic strategies for a variety of disorders in which thrombosis, apoptosis and inflammation contribute to pathogenesis.
Vascular, thrombotic, and inflammatory diseases, such as sepsis, heart attack or stroke, will affect most of us at some point in life, with a profound impact on the quality and duration of life thereafter. Available therapeutic solutions are limited and mortality rates remain unacceptably high. Guided by the encouraging beneficial effects of recombinant activated protein C in sepsis and stroke, the proposed studies will identify novel molecular mechanisms and create engineered molecular variants for translational research and potential safer and more effective therapeutic applications.
|Spronk, H M H; Padro, T; Siland, J E et al. (2018) Atherothrombosis and Thromboembolism: Position Paper from the Second Maastricht Consensus Conference on Thrombosis. Thromb Haemost 118:229-250|
|Griffin, John H; Zlokovic, Berislav V; Mosnier, Laurent O (2018) Activated protein C, protease activated receptor 1, and neuroprotection. Blood 132:159-169|
|Adams, G N; Sharma, B K; Rosenfeldt, L et al. (2018) Protease-activated receptor-1 impedes prostate and intestinal tumor progression in mice. J Thromb Haemost 16:2258-2269|
|Wyseure, Tine; Cooke, Esther J; Declerck, Paul J et al. (2018) Defective TAFI activation in hemophilia A mice is a major contributor to joint bleeding. Blood 132:1593-1603|
|Sinha, Ranjeet K; Wang, Yaoming; Zhao, Zhen et al. (2018) PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke. Blood 131:1163-1171|
|Cooke, Esther J; Zhou, Jenny Y; Wyseure, Tine et al. (2018) Vascular Permeability and Remodelling Coincide with Inflammatory and Reparative Processes after Joint Bleeding in Factor VIII-Deficient Mice. Thromb Haemost 118:1036-1047|
|Mosnier, Laurent O (2018) Warfarin, a juggler's demise. Blood 131:2742-2743|
|Cooke, Esther J; Zhou, Jenny Y; Wyseure, Tine et al. (2018) Erratum to: Vascular Permeability and Remodelling Coincide with Inflammatory and Reparative Processes after Joint Bleeding in Factor VIII-Deficient Mice. Thromb Haemost :|
|Fernández, José A; Xu, Xiao; Sinha, Ranjeet K et al. (2017) Activated protein C light chain provides an extended binding surface for its anticoagulant cofactor, protein S. Blood Adv 1:1423-1426|
|Griffin, John H; Mosnier, Laurent O; Fernández, José A et al. (2016) 2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis: Thrombotic Stroke: Neuroprotective Therapy by Recombinant-Activated Protein C. Arterioscler Thromb Vasc Biol 36:2143-2151|
Showing the most recent 10 out of 40 publications