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Functional genomics of inborn errors and therapeutic interventions in high density lipoprotein metabolism

Objective

Despite considerable progress in prevention and therapy, coronary artery disease remains the most frequent cause of death. High- density lipoproteins (HDL) are promising targets to further reduce morbidity and mortality because low HDL cholesterol plasma concentrations increase cardiovascular risk and because HDL exerts many cardio- and vasoprotective functions. There is also great need in improving the diagnostic and prognostic value of the biomarker HDL cholesterol as HDL function is determined by the quality rather than by the quantity of HDL.

Therefore, this HDLomics project will apply functional genomics approaches including genomics, proteomics and lipidomics as well as new clinical diagnostic tools to study the effects of differential regulation of HDL metabolism on pathophysiological events relevant for atherosclerosis:
1) Using genome wide linkage analysis in families with Mendelian inheritance of low HDL cholesterol we will search new major genes regulating HDL cholesterol.
2) Using high throughput sequencing and allele specific genotyping technology we will elucidate the impact of mutations in candidate genes for the variation of HDL cholesterol as well as other lipid traits and the occurrence of cardiovascular events.
3) Using knock-out and transgenic mouse models we will study the metabolic and vascular impact of mutated candidate genes on HDL metabolism.
4) We will employ proteomic and lipidomic tools for the characterisation of HDL and finding specific effects of mutations or interventions on the structure and function of HDL as well as on lipid metabolism and atherosclerosis.
5. We will develop and evaluate new therapies including gene therapy protocols for the correction of inborn errors of HDL metabolism in humans.

The ultimate goals of HDLomics are hence the identification and validation of new targets, which can be used in differential diagnosis, prognosis, therapy, prevention, and therapy monitoring of low HDL cholesterol and atherosclerosis.

Call for proposal

FP6-2005-LIFESCIHEALTH-6
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Funding Scheme

STREP - Specific Targeted Research Project

Coordinator

UNIVERSITAT ZURICH
Address
Ramistrasse 71
Zurich
Switzerland

Participants (6)

AMSTERDAM MOLECULAR THERAPEUTICS INC.
Netherlands
Address
Meibergdreef 61
Amsterdam
FOUNDATION FOR RESEARCH AND TECHNOLOGY - HELLAS
Greece
Address
Vassilika Vouton
Heraklion
LINKOPING UNIVERSITY
Sweden
Address
Linkoping University
Linkoping
NATIONAL CENTRE FOR SCIENTIFIC RESEARCH "DEMOKRITOS"
Greece
Address
N.c.s.r. "Demokritos"
Agia Paraskevi Attikis
RIGSHOSPITALET, UNIVERSITY OF COPENHAGEN
Denmark
Address
Blegdamsvej 9
Copenhagen
UNIVERSITEIT VAN AMSTERDAM - ACADEMISCH ZIEKENHUIS
Netherlands
Address
Meibergdreef 9
Amsterdam