SOUTH - Application-oriented studies on regulatory networks involved in lipid homeostasis and atherosclerosis (FP6-LIFESCIHEALTH) (2006-10-01 - 2009-09-30) (»add to infobox)

Maurizio CRESTANI, Iannis TALIANIDIS, Gilles SALBERT, Marco BERTOLOTTI, Peter BARATH, Sean MCSWEENEY, Béatrice DESVERGNE, Darren James HART, Paola TARRONI

UNIVERSITA DEGLI STUDI DI MILANO (ITC45 - Milano) (Italy), BIOMEDICAL SCIENCES RESEARCH CENTRE "ALEXANDER FLEMING" (GR300 - Attiki) (Greece), UNIVERSITE DE RENNES 1 (FR523 - Ille-et-Vilaine) (France), UNIVERSITA DEGLI STUDI DI MODENA E REGGIO EMILIA (ITD54 - Modena) (Italy), SLOVENSKA AKADEMIA VIED (SK010 - Bratislavsky kraj) (Slovakia), INSTALLATION EUROPEENNE DE RAYONNEMENT SYNCHROTRON (FR714 - Isère) (France), UNIVERSITE DE LAUSANNE (CH022 - Freiburg) (Switzerland), EUROPAISCHES LABORATORIUM FUER MOLEKULARBIOLOGIE - EMBL (DE125 - Heidelberg, Stadtkreis) (Germany), AXXAM SRL (ITC45 - Milano) (Italy)

Cholesterol and lipid homeostasis is achieved through the action of a complex regulatory network (regulome) that controls the expression of genes involved in these metabolic pathways. Our recent studies suggest that i) high in the hierarchy of the regulatory network is the nuclear receptor HNF4, whose activity on cholesterol metabolism genes is selectively affected by HDAC7 recruitment, and that ii) targeting HDAC7 lowers serum cholesterol levels. Given this premise, the general objective of this proposal is to bridge these new basic science concepts to clinical applications by analysing the transcriptome and the regulome controlling cholesterol and lipid homeostasis and by pharmacologically targeting the HNF4/HDAC7 regulatory axis. We will develop improved strategies for the prevention and treatment of atherosclerosis by pursuing the following specific aims 1.Rational design of high affinity ligands for HNF4 and inhibitors of HDAC7 based on the analysis of their 3D-structures 2.Analysis of the global pattern of gene expression (Transcriptome) and transcription factor network (Regulome) involved in lipid homeostasis in control mice and in mice treated with HDAC inhibitors and HNF4 ligands and definition of their pharmacological profile 3.Development of clinical diagnostic tools The multidisciplinary nature of the proposal will exploit and integrate the expertise in molecular/cell biology, pharmacology, toxicology, medicine, physics/crystallography, chemistry, biochemistry and bioinformatics to identify new molecules affecting lipid metabolism and study their effects on pathophysiological events underlying atherosclerosis Upon completion of the project we expect to a.identify HNF4 ligands and HDAC7 selective inhibitors affecting lipid metabolism b.define the effects of these molecules on the transcription network regulating cholesterol and lipid metabolism and their pharmacological profile c.develop non invasive tools for evaluating the atherosclerotic burden

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