MECHFXR

"Towards FXR-mediated therapeutic intervention: Understanding how FXR integrates metabolic, endocrine and inflammatory signaling."

Coordinatore	UNIVERSITAIR MEDISCH CENTRUM UTRECHT    more  Organization address address: HEIDELBERGLAAN 100 city: UTRECHT postcode: 3584 CX contact info Titolo: Dr. Nome: E.Th. Erik Cognome: Van Den Broek Email: send email Telefono: +31 88 7568172 Fax: +31 88 7553660
Nazionalità Coordinatore	Netherlands [NL]
Totale costo	183˙805 €
EC contributo	183˙805 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2011-IEF
Funding Scheme	MC-IEF
Anno di inizio	2012
Periodo (anno-mese-giorno)	2012-04-01   -   2014-03-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	UNIVERSITAIR MEDISCH CENTRUM UTRECHT  Organization address address: HEIDELBERGLAAN 100 city: UTRECHT postcode: 3584 CX contact info Titolo: Dr. Nome: E.Th. Erik Cognome: Van Den Broek Email: send email Telefono: +31 88 7568172 Fax: +31 88 7553660	NL (UTRECHT)	coordinator	183˙805.80

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 Obiettivo del progetto (Objective)

'Nuclear receptors (NRs) are ligand-activated transcription factors that play vital roles in human physiology. 13% of all FDA-approved drugs target NRs, however they are associated with side-effects that limit their utility and safety. These side-effects are attributed to general activation of all NR transcriptional actions. Understanding the molecular mechanisms of NR transcriptional functions is essential to improve rational NR drug design. This project will focus on FXR, the NR activated by bile salts and key regulator of bile salt, lipid and glucose metabolism via transactivation. FXR also regulates inflammation status via transrepression of NF-κB. Currently, FXR is being investigated as target in the treatment of cholestasis, metabolic syndrome and inflammatory diseases. However, global activation of FXR will likely cause deleterious side-effects. Therefore, the proposed research aims to functionally dissect the different molecular mechanisms of FXR action during ligand-dependent transactivation and transrepression. Post-translational modifications and differentially recruited cofactors are crucial in differentiating between transactivation and transrepression. Key objectives: 1. To investigate the upstream protein modifications in FXR both in vitro and in vivo models. 2. To investigate protein-protein interactions that govern FXR signaling. Innovative unbiased assays that combine SILAC and biotinylated DNA-protein complex precipitations will be used to identify modifications and interacting proteins by mass spectrometry. In a pilot study, The Applicant identified a novel phosphorylation site (FXR-S224), important for gene transactivation but not NF-κB transrepression. These findings could advance drug design for FXR and warrant further investigation. During this fellowship The Applicant will extend her skills in molecular NR pathway analysis, important to establish herself in the NR field and prepare for setting up her own group and accomplishing her career a'

Introduzione (Teaser)

The side-effects of drugs targeting nuclear receptors (NRs) are attributed to non-specific activation of all NR transcriptional actions. Unravelling the molecular mechanisms of NR transcriptional functions is essential to improve rational NR drug design.