CD40-INN SIGNED
CD40 goes innate: defining and targeting CD40 signaling intermediates in the macrophage to treat atherosclerosis
Total Cost €
0EC-Contrib. €
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Project "CD40-INN" data sheet
The following table provides information about the project.
| Coordinator |
ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Organization address contact info |
| Coordinator Country | Netherlands [NL] |
| Total cost | 1˙999˙420 € |
| EC max contribution | 1˙999˙420 € (100%) |
| Programme |
1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC)) |
| Code Call | ERC-2015-CoG |
| Funding Scheme | ERC-COG |
| Starting year | 2016 |
| Duration (year-month-day) | from 2016-12-01 to 2021-11-30 |
Partnership
Take a look of project's partnership.
| # | ||||
|---|---|---|---|---|
| 1 | ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM | NL (AMSTERDAM) | coordinator | 1˙999˙420.00 |
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Project objective
Atherosclerosis, the underlying cause of the majority of cardiovascular diseases (CVD), is a lipid driven, inflammatory disease of the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of atherosclerosis-induced CVD risk remains unaddressed. Therefore, characterizing mediators of the inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications. Co-stimulatory molecules are key players in modulating immune interactions. My laboratory has defined the co-stimulatory CD40-CD40L dyad as a major driver of atherosclerosis. Inhibition of CD40, and of its interaction with the adaptor molecule TRAF6 by genetic deficiency, antibody treatment or (nanoparticle based) small molecule inhibitor (SMI) treatment, is one of the most powerful therapies to reduce atherosclerosis in a laboratory setting. Although CD40-CD40L interactions are associated with adaptive immunity, I recently identified the macrophage as a driver of CD40-induced inflammation in atherosclerosis. We will use state-of-the-art in vitro experiments, live cell-, super resolution imaging, proteomics approaches and mutant mouse models to unravel the role of macrophage CD40 in atherosclerosis. Moreover, using structure based virtual ligand screening, I will develop lead SMIs targeting macrophage CD40-signaling, which I will deliver using macrophage-targeting nanoparticles. My goal is to define the role of macrophage CD40 in inflammation and immunity and disentangle how its activation affects atherosclerosis. I will finally test the feasibility of targeting macrophage CD40-signaling as a treatment for CVD. These studies will define the role of CD40-signaling in the innate immune system in health and (cardiovascular) disease. As components of macrophage CD40-signaling have the potential to be amenable to pharmacological manipulation, we will establish their feasibility as novel targets for (CVD) treatment.
Publications
| year | authors and title | journal | last update |
|---|---|---|---|
| 2017 |
Holger Winkels, Svenja Meiler, Dirk Lievens, David Engel, Charlotte Spitz, Christina Bürger, Linda Beckers, Angelika Dandl, Sigrid Reim, Maiwand Ahmadsei, Helene Hartwig, Lesca M Holdt, Michael Hristov, Remco T A Megens, Martin M Schmitt, Eric A Biessen, Jannie Borst, Alexander Faussner, Christian Weber, Esther Lutgens, Norbert Gerdes CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice published pages: 3590-3599, ISSN: 0195-668X, DOI: 10.1093/eurheartj/ehx517 |
European Heart Journal 38/48 | 2019-09-02 |
| 2018 |
Pascal J.H. Kusters, Tom T.P. Seijkens, Linda Beckers, Dirk Lievens, Holger Winkels, Vivian de Waard, Adriaan Duijvestijn, Moritz Lindquist Liljeqvist, Joy Roy, Alan Daugherty, Andrew Newby, Norbert Gerdes, Esther Lutgens CD40L Deficiency Protects Against Aneurysm FormationHighlights published pages: 1076-1085, ISSN: 1079-5642, DOI: 10.1161/ATVBAHA.117.310640 |
Arteriosclerosis, Thrombosis, and Vascular Biology 38/5 | 2019-09-02 |
| 2018 |
Ellen Rouwet, Esther Lutgens 2016 Jeffrey M. Hoeg Award Lecture published pages: ATVBAHA.118.3077, ISSN: 1079-5642, DOI: 10.1161/ATVBAHA.118.307742 |
Arteriosclerosis, Thrombosis, and Vascular Biology | 2019-09-02 |
| 2018 |
José Tuñón, Magnus Bäck, Lina Badimón, Marie-Luce Bochaton-Piallat, Bertrand Cariou, Mat J Daemen, Jesus Egido, Paul C Evans, Sheila E Francis, Daniel FJ Ketelhuth, Esther Lutgens, Christian M Matter, Claudia Monaco, Sabine Steffens, Erik Stroes, Cécile Vindis, Christian Weber, Imo E Hoefer Interplay between hypercholesterolaemia and inflammation in atherosclerosis: Translating experimental targets into clinical practice published pages: 948-955, ISSN: 2047-4873, DOI: 10.1177/2047487318773384 |
European Journal of Preventive Cardiology 25/9 | 2019-09-02 |
| 2017 |
Suzanne A. B. M. Aarts, Tom T. P. Seijkens, Pascal J. H. Kusters, Susanne M. A. van der Pol, Barbara Zarzycka, Priscilla D. A. M. Heijnen, Linda Beckers, Myrthe den Toom, Marion J. J. Gijbels, Louis Boon, Christian Weber, Helga E. de Vries, Gerry A. F. Nicolaes, Christine D. Dijkstra, Gijs Kooij, Esther Lutgens Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation published pages: , ISSN: 1742-2094, DOI: 10.1186/s12974-017-0875-9 |
Journal of Neuroinflammation 14/1 | 2019-09-02 |
| 2017 |
Pascal Kusters, Tom Seijkens, Christina Bürger, Bart Legein, Holger Winkels, Marion Gijbels, Christian Barthels, Remy Bennett, Linda Beckers, Dorothee Atzler, Erik Biessen, Thomas Brocker, Christian Weber, Norbert Gerdes, Esther Lutgens Constitutive CD40 Signaling in Dendritic Cells Limits Atherosclerosis by Provoking Inflammatory Bowel Disease and Ensuing Cholesterol Malabsorption published pages: 2912-2919, ISSN: 0002-9440, DOI: 10.1016/j.ajpath.2017.08.016 |
The American Journal of Pathology 187/12 | 2019-09-02 |
| 2017 |
Pascal J H Kusters, Esther Lutgens, Tom T P Seijkens Exploring immune checkpoints as potential therapeutic targets in atherosclerosis published pages: 368-377, ISSN: 0008-6363, DOI: 10.1093/cvr/cvx248 |
Cardiovascular Research 114/3 | 2019-09-02 |
| 2018 |
Tom T.P. Seijkens, Claudia M. van Tiel, Pascal J.H. Kusters, Dorothee Atzler, Oliver Soehnlein, Barbara Zarzycka, Suzanne A.B.M. Aarts, Marnix Lameijer, Marion J. Gijbels, Linda Beckers, Myrthe den Toom, Bram Slütter, Johan Kuiper, Johan Duchene, Maria Aslani, Remco T.A. Megens, Cornelis van ‘t Veer, Gijs Kooij, Roy Schrijver, Marten A. Hoeksema, Louis Boon, Francois Fay, Jun Tang, Samantha Baxter, Aldo Jongejan, Perry D. Moerland, Gert Vriend, Boris Bleijlevens, Edward A. Fisher, Raphael Duivenvoorden, Norbert Gerdes, Menno P.J. de Winther, Gerry A. Nicolaes, Willem J.M. Mulder, Christian Weber, Esther Lutgens Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis published pages: 527-542, ISSN: 0735-1097, DOI: 10.1016/j.jacc.2017.11.055 |
Journal of the American College of Cardiology 71/5 | 2019-09-02 |
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