Solving‘the dyslipidemia, immune response and atherosclerosis enigma’ Towards novel treatment for CVD

1. Solving ‘the dyslipidemia, immune response and atherosclerosis enigma’ Towards novel treatment for CVD John Kastelein - AMC Johan Kuiper - LACDR

2. Consortium – PI - Disciplines Vascular Biology, Cardiology, Lipidology, Immunology, Pathology J. Kastelein, E. Stroes W. Jukema, G. Pasterkamp (Epi) Genetics, Bioinformatics, Systems Biology C. Wijmenga, B. Heijmans J.A. Kuivenhoven B. Groen Vascular Biology, Inflammation, Immunology - J. Kuiper, M. van Eck, P. Rensen, E. Biessen - C. de Vries, M. de Winther, E. Lutgens 14 top PIs of the Dutch cardiovas-cular research Community AMC, LUMC, UMCG, UMCU, MUMC Translation

3. Health Care problem Current best practice: 30% CV risk reduction Urgent need for novel feasible drug targets We will satisfy this need through finding – novel - origins of dyslipidemia and premature atherosclerosis and through revealing the effect of dyslipidemia on the immune system.

4. Systems Biology Development of new therapeutic approaches Genetics Dyslipidemia Target identification, pathway analysis target validation and testing Immune response

6. WP1 Dyslipidemia and premature atherosclerosis Patient recruitment State of the art phenotyping Validation of findings in WP2,3,4,5 in patient and prospective cohorts WP3 Immune response Characterize dyslipidemia associated immune responses (focus epigenetics ) Identification of immune pathways and biomarkers WP2 Integrated genetics Identification of novel gene defects through advanced genetic approaches in families and epidemiological cohorts WP5 Translation of findings in WP2,3,4 in mechanistic mouse studies How do mutations cause disease? Identification of novel pathways/biomarkers in state of the art animal models . WP6 Translation of findings in WP2,3,4,5 into novel therapeutic strategies + biomarker validation Strategy (anti-sense, biologicals, immune modulators, antagomirs) testing in animal models WP4 Bioinformatics and Systems Biology Coupling genomics/metabolomics to enhance analysis sensitivity and specificity Modeling dyslipidemia and immune response interaction

9. Perspective Studying the causes (defects in new genes) and consequences of dyslipidemia (effects on immune system) will boost translational atherosclerosis research at the national level and will strengthen our position internationally. We will accelerate the identification and characterization of molecular events that cause CVD and will reveal new targets for pharmaceutical intervention as well as new biomarkers. Such progress will provide an ideal basis for EU consortia that in collaboration with the industry can develop and test new pharmaceutical strategies.