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.