Project number 2

Into the molecular details of a newly discovered anti-inflammatory axis, based on zinc and glucocorticoid receptor

Sepsis is a highly lethal form of acute Systemic Inflammatory Response Syndrome (SIRS), associated with infection. It kills some 6 million people per year worldwide, and the third killing disease worldwide (after cancer and heart disease). After 40 years of intense research, no novel therapeutic breakthroughs for sepsis have reached the bedside, and after 60 consecutive failed clinical trials, sepsis is considered a huge unmet medical need. In sepsis patients, a recurrent deficiency in zinc levels is found, as well as a poor function of the gut and a total lack of response to the standard anti-inflammatory glucocorticoids (GCs).
In mouse models of SIRS, we have found that Zn protects against lethality, and that Zn performs this function via the Metal Transcription Factor 1 (MTF1), but also involves an unexpected, essential contribution of GCs and of the glucocorticoid receptor (GR), without which Zn is unable to protect. The cells of action of this novel pathway are the intestinal epithelial cells (IECs). RNASEQ experiments in IECs of WT and GR mutant mice, show that Zn uses GR to regulate a very specific set of genes, only partly overlapping with the normal GR regulated set of genes suggesting that Zn, via MTF1, stimulates GR in a very specific direction.
This project contains two parts. In the first part, we will make use of mice (tissue specific GR-KO mice, MTF-1-KO mice and other mutant mice) and study the cross talk between Zn-MTF1-GCs-GR at the level of pathophysiology and metabolism in intestinal epithelium. In the second part, based on existing and newly generated transcriptome profiles, we will address the (physical) interaction between the two transcription factors and study how MTF1 leads to a re-direction of the transcriptional output of GR. We will focus of the impact of Zn/MTF1 on GR dimerization, DNA binding and co-factor recruitment. The project will include RNASEQ, CHIPSEQ, MS analysis, qPCR, microscopy etc.
The mouse work and RNASeq experiments will be performed in the lab of Claude Libert. The cross-talk between Zn/MTF1 with GR (and other nuclear receptors such as PPARs) will be performed in the lab of Claude Libert and Jan Tavernier. Determining metabolites and collecting MS data is done in collaboration between Claude Libert and Jan Tavernier and other VIB groups and University groups.
It is expected that the PhD student will spend 50% in the lab of Claude Libert and 50% in the Jan Tavernier lab.

Keywords
food, microbiota, metabolism, inflammation, nuclear receptors

Supervisors
Claude Libert, VIB Inflammation Research Center, UGent, Gent
Jan Tavernier, VIB Medical Biotechnology Center, UGent, Gent