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Deciphering The Molecular Basis Of Gr Cross-Talk With Physiological Partners

Reference : PhD Bruno KLAHOLZ

Offer publication : April 6, 2016

Nuclear receptors represent a family of ligand-dependent transcription factors (48 in human) and most, but not all combine a variable N-terminal domain with a conserved DNA binding domain (DBD) and a C-terminal ligand binding domain (LBD). Many NRs exhibit a function in metabolism with marked immune-regulatory and anti-inflammatory effects. It is particularly the case for the glucocorticoid receptor (GR) that drives potent anti-inflammatory pathways and blocks the activity of key inflammatory transcription factors, such as AP-1 and NF-κB.

However, drugs such as prednisone/dexamethasone that target GR have unwanted metabolic side effects, such as diabetogenicity, hypertension and muscle wasting,
limiting their clinical use. PPARα belongs to the PPARs subfamily of nuclear receptors that are involved in lipid and glucose homeostasis. In addition to stimulating fatty acid oxidation, PPARα agonists (fibrates) have interesting anti-inflammatory actions. Functional cross-talk between
GR and PPARα has been demonstrated in vitro and in vivo and opens promising perspectives to improve the therapeutic effect of anti-inflammatory treatment with lesser side-effects.

The goal of the project is the analysis of the molecular mechanisms governing the regulation of transcription by the GR, using an integrative structural biology approach. The thesis subject will on the one hand focus on the production and purification of recombinant receptors, full and truncated in the
various domains. Alternatively, endogenous GR-associated transcription complexes will be isolated from eukaryotic cells, characterized by mass spectrometry and studied by cryo-electron microscopy (cryo EM). These studies will allow gaining novel insights into the molecular architecture and
topological arrangement of GR bound to target DNA, and of GR-based transcription regulation complexes and obtain structural information on the link between ligand binding and GR architecture. Complexes between GR and PPARα will be further reconstituted and mapping of the interaction regions will be performed. The complexes will be characterized in solution using different biophysical techniques, such as analytical ultracentrifugation and light scattering. High resolution single particle cryo-electron microscopy (cryo EM) studies of GR-associated transcription complexes will be performed, including image processing and 3D reconstruction of the complexes and map interpretation. Concomitantly, crystallization studies will be performed in order to obtain crystals of complexes for further x-ray diffraction studies and high resolution structure refinement.

The project will allow obtaining original information on the architecture of functional GR homodimers and on the molecular mechanisms of cross-talk between GR and PPARα through a combination of structural and biophysical methods. These results will pave the way for the development of novel strategies in the treatment of inflammatory diseases and in the understanding of novel mechanisms of eukaryotic transcriptional regulation.

- WISHED SKILLS : Since the project has a strong interdisciplinary character (integrative structural biology approach), we can welcome a student having either type of Master, including biochemistry, molecular biology, bioinformatics, chemistry, medicine, physics or mathematics, as long as the
candidate is open-minded for learning new technologies; a complementary training will be provided accordingly.

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : Training will be provided in biochemistry and biophysical characterisation of macromolecular complexes, in image data collection using a novel electron microscope recently installed, training in image processing, crystallisation and structure determination by crystallography, integration of functional data.

Your application

Application Deadline : Dec. 31, 2016

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