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
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- medical and health sciences health sciences inflammatory diseases
- medical and health sciences basic medicine medicinal chemistry
- medical and health sciences basic medicine physiology
- natural sciences chemical sciences analytical chemistry mass spectrometry
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2011-IEF
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
3584 CX Utrecht
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.