Characterization Of Androgen And Glucocorticoid Crosstalk In Mammals
Reference : PhD Daniel Metzger
Publication de l'offre : 26 janvier 2018
The steroid hormones androgens and glucocorticoids regulate various signaling pathways in mammals. Androgens control cell proliferation, development of sexual characteristics, as well as muscle mass and strength, whereas glucocorticoids control circadian rhythm, metabolism, and immune functions. These effects are mediated by two ligand-dependent transcription factors, the androgen receptor (AR) and the glucocorticoid receptor (GR), that represent important drug targets for a number of diseases since the receptors activities can be modulated by synthetic agonists and antagonists. However, the clinical use of these compounds is limited by important side effects. For instance, glucocorticoids are largely used as anti-inflammatory agents, but long-term treatments induce diabetes, osteoporosis and muscle wasting. Moreover, even if androgens anabolic effects on skeletal muscle represent an attractive strategy to improve muscle function in patients suffering myopathies, their clinical use is limited by an elevated risk of prostate cancer. Conversely, treatment of metastatic prostate cancer with anti-androgens leads to muscle atrophy, therefore impairing the quality of life of patients. These observations underline the need for AR and GR ligands with increased selective activities, but also indicate that the signaling pathways controlled by androgens and glucocorticoids are potentially interconnected.
Our project aims at providing the molecular basis of gene- and tissue-specific actions of androgens and glucocorticoids, and a molecular understanding of the cross-talk between their signaling pathways in mammalian physiology using an integrative biology approach including genome-wide sequencing of AR- and/or GR-bound DNA sites, transcription assays, and mouse phenotyping. These analyses should provide insights into the oligomeric status of AR and GR bound to various DNA response elements, and delineate the in vivo functions of these receptors in cellular and tissue contexts relevant for clinical applications. Since glucocorticoids are one of the most prescribed therapeutic agent and anti-androgens are the first-line treatment for metastatic prostate cancer, our data will be extremely valuable to develop new ligands with increased specific activities, and thus generate drugs with reduced side effects.
PhD supervisor: Daniel Metzger, DR1 CNRS
Co-supervisor: Delphine Duteil, CRCN, INSERM
Date limite de candidature : 1 novembre 2018