Projects

Since Systemic Inflammatory Response Syndrome (SIRS), such as sepsis, is by definition an inflammatory disease, it is bizarre that Glucocorticoids (GCs) are ineffective in this context. To generate more effective GCs, over the past 25 years, the emphasis has been on the generation of GR ligands that favor GR monomer formation (referred to as SElective GR Agonists, SEGRAs). This has not resulted in a successful therapy. Our observations ...

The androgen receptor (AR: NR3C4) is a transcription factor which plays a central role in the development and maintenance of the male phenotype. This is illustrated by the many AR mutations that have been described in androgen insensitivity syndrome patients. While most of these mutations affect known AR functions like ligand, DNA or co-activator binding, some remained unexplained. We recently described a detailed map of the dimerization ...

Mutations in the androgen receptor found in androgen insensitivity syndrome (AIS) patients provide a wealth of information on the molecular biology of this receptor. Most recently, we described how the ligand-binding domain of the androgen receptor dimerises. The importance of this dimerization is illustrated by the fact that many mutations which are correlated with AIS are predicted to disrupt this interface. To study this further, we will ...

Novel tools to study the importance of dimerization of the GR wil be generated and investigated. Cells and mice will be generated with inducible GR dimerization and these will be used to study the role of GR dimerization in the control of SIRS.

Down Syndrome Cell Adhesion Molecule (DSCAM) belongs to the immunoglobulin (Ig) superfamily of cell-surface receptors and is implicated in cell adhesion and neuronal wiring. The Drosophila Dscam gene can give rise to more than 19,000 distinct ectodomain isoforms through differential splicing in three Ig domains, Ig2, Ig3, and Ig7. The diversity is used to generate a repertoire of homophilic interaction partners, exclusively amongst ...

G-protein coupled receptors (GPCRs) are the eyes and ears of the cell. They are heavily implicated in cell functioning and disease. All GPCRs appear to signal via a few highly conserved pathways, raising the question of how cells maintain signaling specificity. Homo- and hetero-dimerization of GPCRs is thought to be an important regulatory mechanism, though its role remains poorly understood partly due to conflicting experimental ...

In a multicellular organism, all the processes of cell growth, proliferation, movement and apoptosis are strictly regulated by cell signalling. Individual cells receive signals from the environment and from other cells, and adjust their behaviour accordingly. These signals are received by receptor proteins, most of which span the cell membrane and provide a way for signals from outside the cell to cause changes inside the cell. The tyrosine ...

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 ...