Medical and health sciences
- Metabolic diseases
In the EU, 15 million people/yr need systemic glucocorticoids (GCs). GCs, which bind to the glucocorticoid receptor (GR), are effective anti-inflammatories, a.o. against rheumatoid arthritis (RA), but their serious side effects including insulin resistance and dyslipidemia underscore the need for alternative therapeutic strategies. Interestingly, peroxisome-proliferator activated nuclear receptor a (PPARa) agonists counteract symptoms similar to GC side effects. To develop new anti-RA drugs with fewer side effects, I will apply a revolutionary different approach. Rather than seeking novel, individual drug targets, I aim to create novel targets by inducing heterodimerization between GR and PPARa with bivalent ligands (BLs) targeting both receptors. The host lab already discovered that 1) when combined, GR and PPARa agonists have exceptional anti-inflammatory activities but lack adverse metabolic effects and 2) an experimental BL further enhances therapeutic benefit in vivo. I will molecularly characterize a next-generation GR-PPARa BL and map its anti-inflammatory and metabolic profile with reporter gene assays and transcript/protein/secretome analyses in vitro. To enable unambiguous measurements of heterodimer formation, I will develop novel molecular tools. BL’s therapeutic benefit will next be evaluated in male and female mice at basal vs RA conditions. Thus, I will apply an innovative strategy with GR-PPARa BLs to potentially develop anti-RA drugs with fewer side effects.