The role of human genetic variations in neuronal guidance cues in premature atherosclerosis

The molecular basis of premature cardiovascular disease (CVD) is incompletely understood. Adverse endothelial monolayer permeability and leukocyte migration are key features in the onset and progression of atherosclerosis. The ligands and receptors of the Neuronal Guidance Cues (NGCs) have been shown to play a potent and rate-limiting role in atherogenesis in mouse model. Human validation of these preclinical findings, however, is largely lacking. Interestingly, our collaborators at the AMC recently identified a number of putative deleterious mutations in NGC genes in 10 families with premature atherosclerosis.

In this project, the AMC and LUMC research groups will join forces and will use a translational approach to utilize this unique opportunity investigate the role of NGCs in atherosclerosis in human (patho)physiology. At the AMC, using extensive human database searches we will assess the impact of common and rare variations in NGCs related genes on CVD risk and progression. Also, we will validate and extend our evidence for the co-segregation of selected NGCs with features of premature atherosclerosis by expanding the families and assessing the function and plasma levels of the selected NGCs. In parallel, the LUMC research group will perform detailed pre-clinical studies to analyse the impact of wild type and genetic variants of the selected NGCs on endothelial permeability and monocyte diapedesis in innovative in vitro microfluidics models.

The results obtained from these studies will substantiate the role of NGCs in human atherosclerotic disease and may identify NGCs as novel potential therapeutic targets in our strive against CVD.

We facilitate a limited number of internships for undergraduate students. If you’re interested, please contact Janine van Gils (j.m.van_gils@lumc.nl) to discuss the possibilities.