Previous basic research on Protein C, a naturally occurring plasma protein, has been translated into diagnostic and therapeutic tools now used in the clinic. Activated protein C (APC) exerts two major and distinct activities, (1) anticoagulant activity and (2) initiation of cell signaling that activates multiple cytoprotective activities. The cytoprotective actions include anti-apoptotic and anti-inflammatory activities, favorable alterations of gene expression, and stabilization of endothelial barriers. Whereas the antithrombotic actions of APC have long been appreciated, only very recently has the physiologic and pharmacologic importance of APC's direct effects on cells become apparent. According to a recently established, incomplete paradigm, APC's cell signaling involves binding of APC by endothelial protein C receptor (EPCR) combined with protease activated receptor-1 (PAR1) proteolytic activation. Our preliminary data identify an additional novel cell signaling pathway for APC, namely a """"""""reelin-like"""""""" signaling pathway involving ligation of apolipoprotein E Receptor 2 (apoER2) that initiates signaling via the intracellular adaptor protein, disabled-1 (Dab1), and Src-family kinases (Src and Fyn) with subsequent downstream actions via the phosphatidylinositol-3-kinase (PI3K)-Akt survival pathway. We need to understand mechanisms for APC's cell signaling reactions and its multiple cytoprotective effects. The three Specific Aims of this hypothesis-driven project are: 1) to define the structural basis for binding of APC to apoER2;2) to prepare and characterize new APC variants with novel mutations that selectively alter APC's targeting of PAR1 and apoER2;and 3) to clarify molecular mechanisms and the roles for each of the various APC receptors responsible each of APC's direct cytoprotective effects on cells. This proposal will address multiple key questions about APC-receptor interactions. The answers from this basic research project may have direct clinical relevance with substantial impact for both basic and clinical research and with obvious clinical implications.

Public Health Relevance

Previous basic research on plasma Protein C, a naturally occurring plasma protein, was translated into diagnostic and therapeutic tools now used in the clinic. The proposed basic research studies on activated protein C will provide new insights into molecular mechanisms by which it acts directly on the blood vessel lining and on blood cells to prevent damage that can be fatal. The findings may well be translatable into future clinical advances.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052246-17
Application #
8007406
Study Section
Special Emphasis Panel (ZRG1-VH-G (03))
Program Officer
Link, Rebecca P
Project Start
1994-12-18
Project End
2013-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
17
Fiscal Year
2011
Total Cost
$702,913
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Healy, Laura D; Rigg, Rachel A; Griffin, John H et al. (2018) Regulation of immune cell signaling by activated protein C. J Leukoc Biol :
Griffin, John H; Zlokovic, Berislav V; Mosnier, Laurent O (2018) Activated protein C, protease activated receptor 1, and neuroprotection. Blood 132:159-169
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
Martos, Laura; Ramón, Luis Andrés; Oto, Julia et al. (2018) ?2-Macroglobulin Is a Significant In Vivo Inhibitor of Activated Protein C and Low APC:?2M Levels Are Associated with Venous Thromboembolism. Thromb Haemost 118:630-638
Gupta, Naveen; Liu, Roland; Shin, Stephanie et al. (2018) SCH79797 improves outcomes in experimental bacterial pneumonia by boosting neutrophil killing and direct antibiotic activity. J Antimicrob Chemother 73:1586-1594
Prince, Raja; Bologna, Luca; Manetti, Mirko et al. (2018) Targeting anticoagulant protein S to improve hemostasis in hemophilia. Blood 131:1360-1371
Gupta, Naveen; Sinha, Ranjeet; Krasnodembskaya, Anna et al. (2018) The TLR4-PAR1 Axis Regulates Bone Marrow Mesenchymal Stromal Cell Survival and Therapeutic Capacity in Experimental Bacterial Pneumonia. Stem Cells 36:796-806
Amar, Arun Paul; Sagare, Abhay P; Zhao, Zhen et al. (2018) Can adjunctive therapies augment the efficacy of endovascular thrombolysis? A potential role for activated protein C. Neuropharmacology 134:293-301
Deguchi, Hiroshi; Elias, Darlene J; Griffin, John H (2017) Minor Plasma Lipids Modulate Clotting Factor Activities and May Affect Thrombosis Risk. Res Pract Thromb Haemost 1:93-102
Healy, Laura D; Puy, Cristina; Fernández, José A et al. (2017) Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J Biol Chem 292:8616-8629

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