Glucocorticoids (GCs) remain a gold standard in the treatment of chronic inflammatory diseases and

cancer because they can efficiently relieve the inflammation-associated symptoms and kill off immune cells.

However, upon chronic exogenous GC treatment not only the associated side effects, such as diabetes and

osteoporosis, but also the development of therapy resistance, remain cumbersome. Clinical progress is

hampered because the fundamental molecular mechanisms of GR-mediated signaling and gene

transcription are complex and not yet fully resolved.

It has long been a matter of debate whether GCs, which act via the GR, only suppress signs and symptoms

of inflammatory disorders or additionally display disease-modifying properties, yet evidence has steadily

accumulated over the past decade revealing that low doses of GCs indeed slow down the progression of

for example radiological joint destruction in rheumatoid arthritis, renewing the interest in these 'old drugs'

(De Bosscher et al., 2010). Unfortunately, repeated or prolonged use of GCs culminates in a long list of

adverse effects, such as insulin resistance, obesity and osteoporosis, skin thinning, inhibition of wound

repair, growth retardation, muscle weakening, hypertension, and mental disorders. In addition, resistance to

the therapeutic effects of GCs has been recognized in many patients, thereby limiting their treatment

options. Subsequently, efforts have been made towards the development of selective GR ligands, however,

this has not yet resulted in new therapeutic GCs in the clinic.

The main objective of my research proposal for the next 5 years is to develop substantial insights into

the underlying molecular mechanisms by which nuclear receptor ligands are able to combat

inflammatory and particular hematological disorders. The red line through my research is to primarily

resolve mechanisms used by the Glucocorticoid Receptor (GR), which I have been studying since 1995,

supplemented with a study on PPAR receptors, because of a marked potential clinically advantageous

cross-talk when combined with GCs. Emphasis will be put on the design of new strategies for therapeutic

intervention, concomitant with a more favorable side effect profile and aiming to reduce the problem of

resistance to therapy.