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Background: In humans, glucocorticoids (GCs) regulate a broad spectrum of physiologic functions essential for life and exert both genomic and non-genomic actions. The actions of GCs are mediated by the human glucocorticoid receptor (hGR), which has two main isoforms, hGRa and hGR?². The hGRa represents the classic hGR that functions as a ligand-dependent transcription factor, while hGR?² does not bind GCs and exerts a dominant-negative effect upon the hGRa, reducing tissue sensitivity to GCs. The hGR interacts with several molecules, including the non-coding RNA growth arrest-specific 5 (Gas5), which decreases the transcriptional activity of the hGR by preventing its binding to DNA.
Aim: To investigate the molecular mechanisms and clinical implications of the genomic and non-genomic actions of GCs, the in vivo role of hGR?² and Gas5 in reducing tissue sensitivity to GCs, and the role of Gas5 in nutritional disorders.
Workpackages:
- In Workpackage (WP) 1, we will determine the expression levels of Gas5 and specific glucocorticoid target-genes in patients with nutritional disorders.
- In WP2, we will determine the molecular mechanisms through which novel hGR mutations affect glucocorticoid signaling (genomic actions of GCs), and those underlying the non-genomic actions of GCs.
- In WP3, we will investigate the role of hGR?² and Gas5 in vivo using transgenic mice inducibly-expressing hGR?² and Gas5, respectively.
Expected Results: These studies will be the first to:
- delineate the role of Gas5 in the pathogenesis of nutritional disorders;
- elucidate further the genomic actions of GCs;
- determine the molecular mechanisms underlying the non-genomic actions of GCs; and
- determine the in vivo role of hGR?² and Gas5 in physiology and in the pathogenesis of generalized and/or tissue-specific glucocorticoid resistance.
They might also lead to the development of new strategies and/or pharmaceutical approaches for the management of glucocorticoid-treated disorders.
