Focus of research
My research over the last 5 years has focused on how modulation of co-stimulatory pathways and the CD40-CD40L dyad in particular are able to mediate vascular disease, with a major focus on how immune cells (inter)act and which phenotype they display.
Within my laboratory, 3 major research lines exist:
1. Cell-type specific actions of CD40-CD40L signaling.
We performed bone marrow transplantations and adoptive transfer studies with platelets and dendritic cells and found that leukocyte (J Exp Med 2010) and dendritic cell CD40 and platelet CD40L (Blood 2011) are crucial in mediating atherosclerosis via different immune modulatory pathways. In addition, we generated CD40Lfl/fl and CD40fl/fl mice which are currently backcrossed with an array of cell-type specific Cre mice, which will give us additional information on the exact role and communication of the different CD40(L) expressing cell-types.
2. Identification of CD40-CD40L signal transduction pathways in atherosclerosis.
CD40-/- mice received a CD40 transgene with mutations in the respective TRAF-binding sites. Apoe-/- mice deficient in the CD40-TRAF2/3/5 binding site developed normal levels of atherosclerosis, while mice deficient in CD40-TRAF6 signaling hardly developed atherosclerosis, and contained immune regulatory monocytes/macrophages (J Exp Med 2010). We are currently investigating how the different CD40-TRAF interactions in different cell-types and pathologies mediate immune cell phenotype and interactions.
Based on these results, I have, in collaboration with Dr. G. Nicholaes (University of Maastricht), developed and tested small compounds directed against the CD40 binding pocket of TRAF6. Two of these compounds are able to successfully inhibit atherosclerosis development, and I have filed a patent.
3. Identification of the role of other co-stimulatory molecules in atherosclerosis.
We are currently investigating the role of CD27/CD70, GITR and CTLA4 in atherosclerosis. We are analysing plaque extent, phenotype and the immunological status of arteries and lymphoid organs of the respective knock-out mice and inhibitors.
Recent interests in the lab are obesity (ATVB 2011), and HSPCs (this grant). I have invested time and efforts in the last 2 years to integrate these scientific fields in my laboratory. We performed a detailed screening on the role of CD40L in obesity, as well as in HSPC biology. These studies are currently submitted to expert journals.