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Gas6 and protein S pathways in hemostasis, thrombosis and inflammation

English title Gas6 and protein S pathways in hemostasis, thrombosis and inflammation
Applicant Angelillo-Scherrer Anne
Number 153436
Funding scheme Project funding (Div. I-III)
Research institution Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor Inselspital
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.09.2014 - 31.08.2017
Approved amount 600'000.00
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Keywords (5)

Inflammation; vitamin K-dependent protein; Gas6; Protein S; Hemostasis

Lay Summary (French)

Lead
Notre projet est d’étudier le rôle de deux molécules de la signalisation cellulaire dans les interactions entre le sang et les vaisseaux et celles entre les cellules du sang dans des processus vitaux comme la production des globules rouges, l’inflammation, les thromboses et les phénomènes permettant de faire cesser des hémorragies.
Lay summary

Contenu et objectifs du travail de recherche

Les molécules de la signalisation qui nous intéressent sont Growth arrest-specific gene 6 (Gas6) et la protéine S. Gas6 a été décrit à l’origine comme faisant partie d’un groupe de gènes dont l’expression augmente dans les cellules en arrêt de croissance. Depuis, de nombreuses fonctions ont été attribuées à Gas6, la protéine qui est le produit du gène Gas6. Considéré initialement comme un facteur de survie et de croissance, il participe à de nombreuses fonctions cellulaires. Par exemple, il est impliqué dans la production et la différentiation des cellules sanguines, la biologie vasculaire, la fonction cérébrale, la fertilité et la thrombose. La protéine S est un anticoagulant naturel. Les patients qui ont un déficit en protéine S ont un risque augmenté de présenter des thromboses et l’absence complète de protéine S est incompatible avec la vie en l’absence de traitement. La compréhension des fonctions biologiques des ces deux molécules est cependant actuellement limitée.

Le but de ce projet est de mieux comprendre le rôle de Gas6 et de la protéine S en utilisant le modèle de la souris avec la perspective de découvrir de nouvelles cibles pour le traitement de l’anémie, des saignements, des thromboses et des réactions exagérées à l’infection.

Contexte scientifique et social du projet de recherche

Gas6 pourrait être utile comme hémostatique et pour traiter l’anémie. De plus, Gas6, tout comme la protéine S, pourrait empêcher les réactions exagérées qui peuvent entraîner la mort dans le cadre d’une infection très grave.  En outre, des inhibiteurs de Gas6 pourraient prévenir et traiter les thromboses. Les résultats de ce travail pourraient ouvrir des perspectives pour des études cliniques impliquant Gas6, des inhibiteurs de Gas6 ou la protéine S.

Direct link to Lay Summary Last update: 25.08.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Targeting anticoagulant protein S to improve hemostasis in hemophilia.
Prince Raja, Bologna Luca, Manetti Mirko, Melchiorre Daniela, Rosa Irene, Dewarrat Natacha, Suardi Silvia, Amini Poorya, Fernández José A, Burnier Laurent, Quarroz Claudia, Reina Caro Maria Desiré, Matsumura Yasuhiro, Kremer Hovinga Johanna A, Griffin John H, Simon Hans-Uwe, Ibba-Manneschi Lidia, Saller François, Calzavarini Sara, Angelillo-Scherrer Anne (2018), Targeting anticoagulant protein S to improve hemostasis in hemophilia., in Blood, 1.
Microvesicles in vascular homeostasis and diseasesPosition Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology
Ridger V. C., Boulanger C. M., Angelillo-Scherrer A., Badimon L., Blanc-Brude O., Bochaton-Piallat M.-L., Boilard E., Buzas E. I., Caporali A., Dignat-George F., Evans P. C., Lacroix R., Lutgens E., Ketelhuth D. F. J., Nieuwland R., Toti F., Tunon J., Weber C., Hoefer I. E. (2017), Microvesicles in vascular homeostasis and diseasesPosition Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology, in Thrombosis and Haemostasis, 117(7), 1296-1316.
Study of Early Elevated Gas6 Plasma Level as a Predictor of Mortality in a Prospective Cohort of Patients with Sepsis
Stalder Grégoire, Que Yok Ai, Calzavarini Sara, Burnier Laurent, Kosinski Christophe, Ballabeni Pierluigi, Roger Thierry, Calandra Thierry, Duchosal Michel A., Liaudet Lucas, Eggimann Philippe, Angelillo-Scherrer Anne (2016), Study of Early Elevated Gas6 Plasma Level as a Predictor of Mortality in a Prospective Cohort of Patients with Sepsis, in PLOS ONE, 11(10), e0163542-e0163542.
The Gas6-Axl Protein Interaction Mediates Endothelial Uptake of Platelet Microparticles
Happonen Kaisa E., Tran Sinh, Mörgelin Matthias, Prince Raja, Calzavarini Sara, Angelillo-Scherrer Anne, Dahlbäck Björn (2016), The Gas6-Axl Protein Interaction Mediates Endothelial Uptake of Platelet Microparticles, in Journal of Biological Chemistry, 291(20), 10586-10601.

Collaboration

Group / person Country
Types of collaboration
Prof. Ch. Heinis/EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. John Griffin, Scripps Clinic, La Jolla United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Y. Matsumura, Division of Developmental Therapeutics, Research Centre for Innovative Oncology Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr F. Saller, Université Paris-Sud France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr Daniela Melchiorre, University of Florence, Florence Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr M. Manetti, University of Florence, Florence Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ISTH 2017 Congress Poster Complete Protein S Deficiency and Pregnancy Outcome in Murine Model 08.07.2017 Berlin, Germany Dewarrat Natacha; Quarroz Claudia; Prince Raja; Reina Caro Maria Desiré; Angelillo-Scherrer Anne;
ISTH 2017 Congress Poster Complete Protein S Deficiency and Pregnancy Outcome in Murine Model 08.07.2017 Berlin, Germany Dewarrat Natacha; Prince Raja; Angelillo-Scherrer Anne; Reina Caro Maria Desiré;
Annual meeting of the Swiss Society for Hematology 2017 Talk given at a conference Effect of complete lack of protein S on pregnancy outcome in mice 04.05.2017 Lausanne, Switzerland Dewarrat Natacha; Angelillo-Scherrer Anne; Reina Caro Maria Desiré; Prince Raja;
Annual Meeting of the Swiss Society of Hematology 2017 Poster Evaluation of the hemostatic profile in mouse models of advanced chronic liver disease 04.05.2017 Lausanne, Switzerland Dewarrat Natacha; Prince Raja; Angelillo-Scherrer Anne; Reina Caro Maria Desiré; Quarroz Claudia;
61st Annual Meeting of the Society of Thrombosis and Hemostasis Research Talk given at a conference Targeting anticoagulant protein S to achieve hemostasis in hemophilia 15.02.2017 Bâle, Switzerland Prince Raja; Quarroz Claudia; Angelillo-Scherrer Anne;
61st Annual Meeting of the Society of Thrombosis and Hemostasis Research Poster Protein S and purpura fulminans 15.02.2017 Bâle, Switzerland Angelillo-Scherrer Anne; Prince Raja;
61st Annual Meeting of the Society of Thrombosis and Hemostasis Research Talk given at a conference Possibilities to rebalance hemostasis in hemophilia 15.02.2017 Bâle, Switzerland Angelillo-Scherrer Anne;
58th ASH Annual Meeting Talk given at a conference Blocking Protein S Improves Hemostasis in Hemophilia a and B 03.12.2016 San Diego, United States of America Prince Raja; Angelillo-Scherrer Anne;
48. Jahrestagung, Deutsche Gesellschaft für Transfusionsmedizin und Immunhämatologie Talk given at a conference Role of protein S ad Gas6 in the development of purpura fulminans 17.09.2016 Bâle, Switzerland Angelillo-Scherrer Anne;
Annual meeting of the Swiss Society for Hematology 2016 Talk given at a conference Protein S induced Purpura fulminans, What's new? Annual meeting for Swiss Society for Hematology. 26.05.2016 Bâle, Switzerland Angelillo-Scherrer Anne; Prince Raja;
Annual Meeting of the Swiss Society of Hematology 2016 Individual talk Elevated Gas6 plasma level and risk of venous thromboembolism recurrence, major bleeding and mortality in elderly patients 25.05.2016 Bâle, Switzerland Angelillo-Scherrer Anne;
57th ASH Annual Meeting and Exposition Poster Role of Protein S and Gas6 in the Development of Purpura Fulminans 05.12.2015 Orlando, United States of America Prince Raja; Angelillo-Scherrer Anne;
ISTH 2015 Congress Poster Alternative strategy to treat hemophilia through protein S inactivation: insight from a mouse model 20.06.2015 Toronto, Canada Angelillo-Scherrer Anne; Prince Raja;


Awards

Title Year
S. Calzavarini, L. Bologna, R. Prince, M. Manetti, D. Melchiorre, I. Rosa, N. Dewarrat, P. Amini, J.A. Fernandez, C. Quarroz, Y. Matsumura, J. A. Kremer Hovinga, J.H. Griffin, H.-U. Simon, L. Ibba Maneschi, F. Saller, A. Angelillo-Scherrer (Switzerland, Italy, United States, Japan, France) Targeting anticoagulant protein S to achieve hemostasis in hemophilia Best oral communication in the field of hemostasis, 61st Annual Meeting of the Society of Thrombosis and Hemostasis Research 2017 2017
R. Prince, L. Bologna, M. Manetti, D. Melchiorre, I. Rosa, N. Dewarrat, P. Amini, J.A. Fernandez, C. Quarroz, Y. Matsumura, J.A. Kremer Hovinga, J.H. Griffin, S. Hans-Uwe, L.I. Manneschi, F. Saller, S. Calzavarini, and A. Angelillo-Scherrer. Blocking protein S to acheive Hemostasis in hemophilia A and B. 58th Annual meeting of American Society of Hematology, 2016. Abstract distinction: Best of ASH, ASH highlight 2017. Blood 2016 128:79. 2016
R. Prince, L. Bologna, M. Manetti, D. Melchiorre, I. Rosa, N. Dewarrat, P. Amini, J.A. Fernandez, C. Quarroz, Y. Matsumura, J.A. Kremer Hovinga, J.H. Griffin, S. Hans-Uwe, L.I. Manneschi, F. Saller, S. Calzavarini, and A. Angelillo-Scherrer. Blocking protein S to achieve hemostasis in hemophilia. Annual meeting of Swiss Society for Hematology, 2016. Award : Roche Award for Best abstracts in hemostasis & vascular biology. 2016

Patents

Title Date Number Inventor Owner
Use of specific siRNA against Protein S for the treatment of hemophilia 02.11.2017 PCT/EP2017/078107

Associated projects

Number Title Start Funding scheme
173127 Gas6 and protein S pathways in hemostasis, thrombosis and inflammation 01.09.2017 Project funding (special)
135822 Role of Gas6 and protein S pathways in hemostasis, thrombosis and inflammation 01.04.2011 Project funding (Div. I-III)
139470 The Swiss Venous Thromboembolism Cohort 65+ (SWITCO-65+) 01.04.2012 Cohort Studies Large
122659 The swiss venous thromboembolism cohort 65+ (SWITCO-65+) 01.04.2009 Cohort Studies Large
135822 Role of Gas6 and protein S pathways in hemostasis, thrombosis and inflammation 01.04.2011 Project funding (Div. I-III)

Abstract

We intend to further study the role of growth arrest-specific gene 6 (Gas6) and protein S (Pros), their mechanism of action and the possible therapeutic use of Gas6 agonists or antagonists in medically important -often lifethreatening- conditions such as bleeding, thrombosis and inflammation. Gas6 belongs to the vitamin K-dependent protein family. Apart from a ?-carboxyglutamic acid-domain interaction with phospholipid membranes, Gas6 also binds as a ligand to the receptor tyrosine kinases Tyro3, Axl and Mer (or TAM receptors) by its carboxy-terminal globular domains. We became interested in Gas6 because of its sequence homology with the anticoagulant Pros. Pros is well recognized as an important natural anticoagulant. This is evidenced by the increased risk of thromboembolic events (recurrent deep vein thrombosis at adult age) in heterozygous patients deficient in Pros. Notably homozygous Pros deficiency is associated with dramatic clinical manifestations (disseminated intravascular coagulation, purpura fulminans) and, if untreated, is incompatible with life. Current knowledge on the biological functions of Pros is only limited, although a number of in vitro studies have helped elucidate the structure/function relationships of Pros.Even though our initial studies of the Gas6 gene inactivation did not reveal any “spontaneous” phenotype, detailed analyses of these mice have unveiled that Gas6 plays an “amplifier” role in hemostasis where it is redundant for baseline hemostasis but critical for effective platelet aggregation upon vascular injury -precisely by amplifying the platelet aggregation activity of the classical agonists. Similarly, we found very recently that Gas6 amplifies erythropoietin responses during compensatory erythropoietic response to anemia. Thus, Gas6 belongs to a novel class of molecules, which are redundant for normal homeostasis but critical for stress-responses. Not surprisingly, therefore, inactivation of Gas6 does not cause life-threatening developmental defects, but may importantly modulate the severity of disease related phenotypes.The first part of the project aims at a better understanding of the in vivo role of Pros in mice. We recently described the lethal prothrombic phenotype of Pros-/- mice. To circumvent the problem of life incompatibility and thereby extend the field of our investigations, mice with very low levels of Pros will be generated. Mice with consistently lower Pros levels would be viable while presenting a much stronger phenotype than that of Pros+/- mice. Such mice would be very helpful to investigate new biological functions for Pros. Two experimental approaches have been chosen: 1) the selective repression of Pros expression in the liver parenchymal cells which is expected to result in dramatic reduction of circulating Pros levels, as Pros is mainly expressed in the liver; 2) the repression of Pros expression in adult mice. Another elegant way to circumvent the embryonically lethal phenotype of Pros-/- mice would be to generate mice with total deficiency in Pros but expressing high levels of activated protein C (APC) or low tissue factor levels. Mice expressing high plasma levels of APC (APChigh) will be therefore crossed with Pros+/- mice to generate Pros+/--APChigh mice, which will be in turn intercrossed to generate Pros-/--APChigh mice. The viability and prothrombic phenotype of the latter mice will be investigated. Conditional Pros knockout mice will also allow us to specifically repress Pros expression in various tissues. Indeed, Pros is not only expressed in the liver but is expressed by endothelial cells, megakaryocytes and contained at high levels in circulating platelets. The contribution of platelet and endothelial Pros to thrombosis and inflammation will be investigated by crossing ProsLox/Lox mice to mice where Cre expression is under the control of platelet- and endothelium-specific promoter, respectively. In the longer run, generation of other tissue-specific Pros knockout mice will allow us to investigate the ability of Pros to function as a ligand of receptors tyrosine kinase of the Tyro3 family (TAM) in various cell types and biological processes.The second part of the project aims at a better understanding of the in vivo role of Gas6 and Pros pathways in platelet function in mice lacking Gas6 or any TAM receptors. In addition, as we found that the lack of one TAM receptor is responsible for a more severe phenotype than the lack of Gas6 itself, we hypothesize that a second ligand might be present in platelets. Pros is present in platelet ? granules from which it is secreted upon platelet activation. However, its role in platelet function is unknown. Therefore, we will study the role of Pros in platelet function. For this investigation, we have chosen to generate mice deficient in Pros only in platelets and study their platelet function in vitro and in vivo. If mice lacking Pros in their platelets have a platelet dysfunction, we will intercross them with Gas6 deficient mice or mice lacking Gas6 only in platelets to see if the platelet defect intensity correspond to that of mice lacking Gas6 alone or one or more of TAM receptors. We will also study the Gas6/Pros pathway in patients suffering from platelet dysfunction or thrombotic disorders.The third part of the project will be dedicated to the study of the role of Gas6/Pros pathway in inflammation in relationship with hemostasis. We found that Gas6, when secreted by monocytic cells in response to endotoxin dampens cytokine release from these cells. In sharp contrast, Gas6 deficient endothelial cells respond to TNF-? without increases in adhesion molecules and tissue factor exposure (the primary initiator of coagulation) and leukocytes transmigrate less extensively through them than through wild-type endothelial cells. Based on these observations, we will complete our studies on the role of Gas6 in inflammation by investigating the influence of Gas6/Pros pathway on coagulation parameters during endotoxemia and infection by using conditional tissue specific mice lacking Gas6, Pros, or one or more of the TAM receptors and by investigating Gas6/Pros pathway in the Lausanne sepsis cohort. Besides, we will further investigate another complication of inflammation involving Gas6, the anemia of chronic diseases and the potential role of Gas6/Pros in iron metabolism.In conclusion, our proposal aims at a better understanding of Gas6/Pros pathway in mechanisms of hemostasis, thrombosis and inflammation. Perspectives of this proposal include clinical trials implying Gas6 agonists or antagonists to treat human diseases such as bleeding disorders, thrombosis or sepsis.
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