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CD40-INN SIGNED

CD40 goes innate: defining and targeting CD40 signaling intermediates in the macrophage to treat atherosclerosis

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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
address: MEIBERGDREEF 15
city: AMSTERDAM
postcode: 1105AZ
website: www.amc.nl

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 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.

# participants  country  role  EC contrib. [€] 
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
List of publications.
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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