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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 173127
Funding scheme Project funding (special)
Research institution Department for BioMedical Research Experimentelle Hämostase Universität Bern
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.09.2017 - 31.08.2021
Approved amount 800'000.00
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Keywords (5)

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

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.A plus long terme, nous prévoyons de développer des agonistes et des antagonistes de ces deux molécules à but thérapeutique.
Lay summary

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.

But

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.

Signification

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, la protéine S ainsi que des inhibiteurs de Gas6 ou de la protéine S.

Direct link to Lay Summary Last update: 07.09.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus
Calzavarini Sara, Prince-Eladnani Raja, Saller François, Bologna Luca, Burnier Laurent, Brisset Anne C., Quarroz Claudia, Reina Caro Maria Desiré, Ermolayev Vladimir, Matsumura Yasuhiro, Fernández José A., Hackeng Tilman M., Griffin John H., Angelillo-Scherrer Anne (2020), Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus, in Blood, 135(22), 1969-1982.
Thrombin generation measurement using the ST Genesia Thrombin Generation System in a cohort of healthy adults: Normal values and variability
Calzavarini Sara, Brodard Justine, Quarroz Claudia, Maire Livia, Nützi Raphael, Jankovic Jovana, Rotondo Laura C., Giabbani Evelyne, Fiedler Georg Martin, Nagler Michael, Angelillo-Scherrer Anne (2019), Thrombin generation measurement using the ST Genesia Thrombin Generation System in a cohort of healthy adults: Normal values and variability, in Research and Practice in Thrombosis and Haemostasis, 3(4), 758-768.
A high Gas6 level in plasma predicts venous thromboembolism recurrence, major bleeding and mortality in the elderly: a prospective multicenter cohort study
Schnegg‐Kaufmann Annatina, Calzavarini Sara, Limacher Andreas, Mean Marie, Righini Marc, Staub Daniel, Beer Juerg‐Hans, Frauchiger Beat, Osterwalder Joseph, Kucher Nils, Matter Christian M., Husmann Marc, Banyai Martin, Aschwanden Markus, Mazzolai Lucia, Hugli Oliver, Nagler Michael, Daskalakis Michael, Rodondi Nicolas, Aujesky Drahomir, Angelillo‐Scherrer Anne (2019), A high Gas6 level in plasma predicts venous thromboembolism recurrence, major bleeding and mortality in the elderly: a prospective multicenter cohort study, in Journal of Thrombosis and Haemostasis, 17(2), 306-318.
Alternatively spliced tissue factor levels are elevated in the plasma of patients with chronic liver diseases
Caversaccio Nathalie I., Reina Caro Maria D., Prince Raja, Müller Martin, Lewis Clayton S., Bogdanov Vladimir Y., Dufour Jean-François, Angelillo-Scherrer Anne (2018), Alternatively spliced tissue factor levels are elevated in the plasma of patients with chronic liver diseases, in European Journal of Gastroenterology & Hepatology, 30(12), 1470-1475.
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, 131(12), 1360-1371.

Collaboration

Group / person Country
Types of collaboration
Silence Therapeutics Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Industry/business/other use-inspired collaboration
Jean-François Dufour, Hepatology, Bern University Hospital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Drahomir Aujesky, Internal Medicine, Bern University Hospital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
John H. Griffin, Scripps Clinic, La Jolla, CA United States of America (North America)
- 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
Meeting of the American Society of Hematology 2019 Poster Gas6 targeting promotes major bleeding and aggravates inflammation in protein S deficient mice 06.12.2019 Orlando, United States of America Angelillo-Scherrer Anne; Prince Raja; Quarroz Claudia;
Meeting of the International Society for Thrombosis and Hemostasis 2019 Poster Thrombin generation measurement using the automated ST Genesia Thrombin Generation System in healthy adulty and some adult patients 06.07.2019 Melbourne, Australia Angelillo-Scherrer Anne; Quarroz Claudia;
Meeting of the International Society for Thrombosis and Hemostasis 2019 Individual talk Platelet but not plasma protein S limits thrombus growth in large veins but not in large arteries by controlling coagulation in situ 06.07.2019 Melbourne, Australia Prince Raja; Quarroz Claudia; Angelillo-Scherrer Anne;
Meeting of the International Society for Thrombosis and Hemostasis 2019 Individual talk Targeting protein S protects mice with hemophilia A from acute and chronic hemarthrosis 06.07.2019 Melbourne, Australia Quarroz Claudia; Prince Raja; Angelillo-Scherrer Anne;
Meeting of the Society for Thrombosis and Hemostasis Research (GTH) 2018 Poster Monitoring the hemostatic balance in a murine model of hepatotoxin-induced advanced chronic liver disease: effects of protein S and combined Gas6-protein S deficiencies 20.02.2018 Vienna, Austria Prince Raja; Quarroz Claudia; Angelillo-Scherrer Anne;
Meeting of the Society for Thrombosis and Haemostasis Research (GTH) 2018 Poster Pregnancy outcome in mice with protein S complete deficiency 20.02.2018 Vienna, Austria Quarroz Claudia; Angelillo-Scherrer Anne; Prince Raja;
Meeting of the American Society of Hematology 2017 Poster Alternatively spliced tissue factor levels in the plasma of patients with liver fibrosis, liver cirrhosis and hepatocellular carcinoma: a single-center retrospective study 09.12.2017 Atlanta, United States of America Angelillo-Scherrer Anne; Prince Raja;
Meeting of the American Society of Hematology 2017 Individual talk Elevated Gas6 plasma level as a predictor of venous thromboembolism recurrence and mortality in a prospective multicenter cohort of elderly patients with venous thromboembolism 09.12.2017 Atlanta, United States of America Angelillo-Scherrer Anne;
Meeting of the American Society of Hematology 2017 Poster Evaluation of the hemostatic profile in mice with chronic liver disease: effects of protein S an combined protein S and Gas6 deficiencies 09.12.2017 Atlanta, United States of America Quarroz Claudia; Prince Raja; Angelillo-Scherrer Anne;


Awards

Title Year
Abstract Achievement Award, American Society of Hematology 2017 to A. Schnegg-Kaufmann (A. Angelillo-Scherrer is last author of the abstract). 2017
Best abstract in the field of hemostasis, Society for Thrombosis and Hemostasis Research, 2017. A. Angelillo-Scherrer is last author of the abstract; C. Quarroz and R. Prince are co-author of the abstract. 2017

Associated projects

Number Title Start Funding scheme
122659 The swiss venous thromboembolism cohort 65+ (SWITCO-65+) 01.04.2009 Cohort Studies Large
153436 Gas6 and protein S pathways in hemostasis, thrombosis and inflammation 01.09.2014 Project funding (Div. I-III)
139470 The Swiss Venous Thromboembolism Cohort 65+ (SWITCO-65+) 01.04.2012 Cohort Studies Large
183501 Installing a Hyperion CyTOF mass cytometry platform for high-dimensional single cell analysis at the University of Bern 01.10.2019 R'EQUIP

Abstract

1.1BackgroundWe intend to further study the role of protein S (Pros) and growth arrest-specific gene 6 (Gas6), their mechanism of action and the possible therapeutic use of Pros/Gas6 agonists or antagonists in medically important -often lifethreatening- conditions such as bleeding, thrombosis and inflammation. Both Pros and Gas6 belong to the vitamin K-dependent protein family. Apart from a gamma-carboxyglutamic acid-domain interaction with phospholipid membranes, Pros and Gas6 also bind to the receptor tyrosine kinases Tyro3, Axl and Mer (or TAM receptors) by their carboxy-terminal globular domains. Pros is an important natural anticoagulant. This is evidenced by the fact that homozygous PROS1 deficiency promotes dramatic clinical manifestations including disseminated intravascular coagulation and purpura fulminans that, if untreated, are incompatible with life. Heterozygous patients deficient in PROS1 have an increased risk of thromboembolic events. Gas6 is redundant for normal homeostasis but critical for stress-responses. Therefore, inactivation of Gas6 does not cause life-threatening developmental defects, but modulates the severity of disease related phenotypes. We generated and studied different models of Pros1 deficient mice as well as Gas6 deficient mice bringing consistent insights into the role of Pros/Gas6 in hemostasis and inflammation. One important part of our pre-clinical studies of these last 3 years allowed us to demonstrate that targeting anticoagulant Pros is a valuable approach for hemophilia therapy. 1.2Specific aims(1) To further investigate the regulation of the hemostatic balance by Pros; (2) to study further the role of Pros/Gas6 in inflammation especially in its relationship with hemostasis/thrombosis and in anemia of chronic diseases, (3) to investigate patients with a defect in Gas6 or TAM receptors and develop Pros/Gas6 agonists or antagonists for therapy.1.3Project descriptionIn the first part of the project, we will use different approaches to circumvent the embryonically lethal phenotype of Pros1-/- mice. We will generate mice with total deficiency in Pros1 but expressing high levels of activated protein C (APChigh mice) or low tissue factor (TF) levels or no factor XI (F11) or XII (F12). The viability and prothrombic/bleeding phenotype of the latter mice will be investigated. Conditional Pros1 knockout mice will also allow us to specifically repress Pros expression in various tissues. The effect of this tissue-specific reduced expression on the APChigh, low TF as well as F11 or F12 deficiency phenotypes will be investigated. We would also study mice lacking both Pros1 and Tfpi to determine to which extent the double knockout phenotype differs from that of both single knockouts. Another interesting subject implying modifications of the hemostatic balance is the chronic liver diseases (CLD). We will therefore apply models of CLD to our transgenic mice. Better understanding the pathophysiology of hemostasis in CLD will allow us to propose diagnostic tests capable to predict bleeding/thrombosis in patients with this disease. In addition, such approach may allow us to identify therapeutic targets. The second part of the project will be dedicated to the continuation of the study of the role of Pros/Gas6 pathways in inflammation in relationship with hemostasis in conditions where histones and neutrophil extracellular traps (NETs) are also involved. Besides, we will further investigate the anemia of chronic diseases in this context and the potential role of Pros/Gas6 in iron metabolism.The third part of the project aims at identifying and study patients with defects in Gas6 and TAM receptors and to develop Pros/Gas6 agonists or antagonists for therapy.1.4Expected value of the proposed projectWe aim at a better understanding of Pros/Gas6 pathways in mechanisms of hemostasis, thrombosis and inflammation. Perspectives include clinical trials implying Pros/Gas6 agonists or antagonists to treat human diseases such as bleeding disorders, thrombosis or sepsis. More specifically, collaborative work with industry will be set up to go head and concretely evaluate Pros targeting for hemophilia treatment.
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