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The Study Of The Molecular Basis Of The Crosstalk Between The Glucocorticoid Receptor And Physiological Partners Offers Perspectives In The Development Of Novel Anti-Inflammatory Therapeutics

Reference : PhD Bruno Klaholz

Publication de l'offre : 26 janvier 2018

PhD Supervisor : Isabelle Billas     billas@unistra.fr

Nuclear receptors (NRs) 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 with unwanted metabolic side effects, such as diabetogenicity, hypertension and muscle wasting. Important functional cross-talk of GR with other nuclear receptors has been demonstrated in vitro and in vivo, in particular with the peroxisome-proliferator activated receptor (PPARα), involved in involved in lipid and glucose homeostasis, and with the androgen receptor (AR) that not only control sexual characteristics, but also muscle functions. These new data open 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 will focus on the production and purification of recombinant receptors, full or as domains. These studies will first focus on GR alone using a cryo-electron microscopy (cryo EM) approach. The results will allow gaining novel insights into the molecular architecture and topological arrangement of GR bound to target DNA and obtain structural information on the link between ligand binding and GR architecture. Complexes between GR and or AR or 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 other NRs 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

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