presentatie prof. kastelein en prof. kuiper
DESCRIPTION
Solving‘the dyslipidemia, immune response and atherosclerosis enigma’ Towards novel treatment for CVDTRANSCRIPT
Solving‘the dyslipidemia, immune response
and atherosclerosis enigma’
Towards novel treatment for CVD
John Kastelein - AMCJohan 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. HeijmansJ.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
Translation
14 top PIs of the Dutch cardiovas-cular research Community
AMC, LUMC, UMCG, UMCU, MUMC
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
Immune response
Target identification, pathway analysisTarget identification, pathway analysistarget validation andtarget validation and
testingtesting
Research questions
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.
Aims•discovery of novel genes causing extreme dyslipidemia or premature atherosclerosis using a novel genomic-metabolomic approach•elucidation of dyslipidemia-associated immune responses focusing on epigenetic mechanisms•disease pathway interactome analysis using advanced Systems Biology•pathway unraveling in state of the art animal models•translating and validating outcomes in patient and epidemiological cohorts•developing novel therapeutic approaches
WP1Dyslipidemia and
premature atherosclerosis
Patient recruitment State of the art phenotyping
Validation of findings in WP2,3,4,5 in patient and prospective cohorts
WP3Immune response
Characterize dyslipidemia associated immune responses (focus
epigenetics)
Identification of immune pathways and biomarkers
WP2Integrated 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.
WP6Translation of findings in
WP2,3,4,5 into novel therapeutic strategies +
biomarker validation
Strategy (anti-sense, biologicals, immune modulators, antagomirs)
testing in animal models
WP4Bioinformatics and Systems
Biology
Coupling genomics/metabolomics to enhance analysis sensitivity and
specificityModeling dyslipidemia and immune
response interaction
Translation
• The function of (new) genes causing dyslipidemia and/or immune responses in humans will be translated to mechanistic mouse studies.
• The outcome of mechanistic studies on the effect of dyslipidemia on the immune system will be validated in patient cohorts.
• Emerging biomarkers will be evaluated in available cohorts.• All new and additional insights into the molecular
pathophysiology of atherosclerosis will be exploited for intervention.
Focus areas Dutch Heart Foundation
Focus on aging and metabolism•C. Wijmenga & A.K. Groen are directly involved in Systems Biology Centre for Energy Metabolism and Aging
Gender issues•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•4 out of 14 PI’s are female
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.