Solving ‘the dyslipidemia, immune response and atherosclerosis enigma’ Towards novel treatment for CVD John Kastelein - AMC Johan Kuiper - LACDR
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
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.
Systems Biology Development of new therapeutic approaches Genetics Dyslipidemia Target identification, pathway analysis target validation and testing Immune response
Research questions <ul><li>Dyslipidemia and inflammation are the two major drivers of CVD. However, the causes of these atherogenic processes and their interactions are only partly understood and unraveled. </li></ul><ul><li>Aims </li></ul><ul><li>discovery of novel genes causing extreme dyslipidemia or premature atherosclerosis using a novel genomic-metabolomic approach </li></ul><ul><li>elucidation of dyslipidemia-associated immune responses focusing on epigenetic mechanisms </li></ul><ul><li>disease pathway interactome analysis using advanced Systems Biology </li></ul><ul><li>pathway unraveling in state of the art animal models </li></ul><ul><li>translating and validating outcomes in patient and epidemiological cohorts </li></ul><ul><li>developing novel therapeutic approaches </li></ul>
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
Translation <ul><li>The function of (new) genes causing dyslipidemia and/or immune responses in humans will be translated to mechanistic mouse studies. </li></ul><ul><li>The outcome of mechanistic studies on the effect of dyslipidemia on the immune system will be validated in patient cohorts. </li></ul><ul><li>Emerging biomarkers will be evaluated in available cohorts. </li></ul><ul><li>All new and additional insights into the molecular pathophysiology of atherosclerosis will be exploited for intervention. </li></ul>
Focus areas Dutch Heart Foundation <ul><li>Focus on aging and metabolism </li></ul><ul><li>C. Wijmenga & A.K. Groen are directly involved in Systems Biology Centre for Energy Metabolism and Aging </li></ul><ul><li>Gender issues </li></ul><ul><li>CVD affects both genders equally, but some immunological pathways have shown differential effects on atherosclerosis in mouse studies and these pathways will be evaluated in the available cohorts </li></ul><ul><li>4 out of 14 PI ’s are female </li></ul>
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.