A profound study of the mechanism and field of application of the increase of Glucocorticoid Receptor transcriptional activity by zinc. (3G013416)
We aim to find a treatment for systemic inflammatory response syndrom (SIRS), which is an often fatal acute condition occuring after serious trauma, bleeding, burning and infection (sepsis). Despite SIRS is an inflammatory condition, anti-inflammatory glucocorticoids (GCs) have no therapeutic benefit in SIRS. GCs bind to the GC receptor GR. Our work in mouse SIRS models show that GCs might have therapeutic future in SIRS if we find a way to stimulate the GR dimer rather than the GR monomer pathway. A GR dimer functions as a true transcription factor, binding GRE DNA elements and inducing gene transcription. In SIRS, this dimer pathway is inactivated. We found that zinc (Zn) protects in a mouse model of SIRS and that the effect of zinc needs GR dimerization. Here, we want to find the mechanism by which Zn helps GCs in stimulating the GR dimer pathway. Our data suggest a direct effect of Zn on the GR dimerization process, which will be further studied in work package 1 (WP1) and at several levels of the GR dimer pathway (dimerization, DNA binding, co-factor recruitment, GRE-gene induction). In WP2, we will study the involvement of the primary Znrecognizing Metal Transcription Factor-1 (MTF-1) in these processes using MTF-1-KO cells and mice and in WP3, we will study the impact of Zn on the gut, the primary target in SIRS, by studying gene expression in relation to GCs and the microbiome. WP4 addresses therapeutic options for Zn to help GCs in GC resistant SIRS and sepsis.