This project aims at elucidating molecular mechanisms of cell- and tissue-specific modulation of corticosteroid hormone action. It focuses on investigating the consequences of impaired corticosteroid responses for patho-physiological processes and contributes to the assessment of small-molecule effectors for potential therapeutic applications.

Various diseases such as diabetes, atherosclerosis, hypertension, heart failure, cataract, mood disorders, osteoporosis and cancer have been associated with disturbed mineralo- and glucoccorticoid-mediated responses. Mineralo- and glucocorticoid action is tissue-specifically regulated by 11beta-hydroxysteroid dehydrogenases (11HSDs). 11HSD1 converts inactive (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone). Recent studies causally linked elevated 11HSD1 activity with the metabolic syndrome, and inhibition of 11HSD1 is considered as promising therapeutic approach. We showed on a cellular level that 11HSD1 activity depends on the availability of cosubstrate NADPH and glucose. 11HSD2 catalyzes the reverse reaction and prevents cortisol-induced MR activation. We showed that reduced 11HSD2 activity due to genetic defects, decreased transcriptional expression or the presence of inhibitors results in enhanced activation of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR).

The proposed research aims at elucidating the molecular mechanisms underlying the coupling of cellular energy state and local glucocorticoid activation by 11HSD1. The impact of intracellular glucose-6-phosphate (G6P) and the role of G6P-transporter (G6PT) and glucose-6-phosphatase (G6Pase) on local glucocorticoid activation will be studied. In addition, the impact of the G6PT/G6Pase/H6PDH/11HSD1 system on the differentiation of adipocytes and myocytes will be investigated. Furthermore, we aim at elucidating the influence of cellular stresses (redox changes, reactive oxygen species (ROS), ATP depletion, unfolded protein response, presence of pro-inflammatory cytokines) on the function of 11HSDs and on MR and GR activation in different cell types.

In previous studies, we addressed aspects important for the safety assessment of 11HSD1 inhibitors, including species-specific functions and assessment of compound selectivity. Here, we aim at extending these approaches by studying potential effects of 11HSD1 inhibitors on the hepatic metabolism of xenobiotics and by considering structural aspects, ligand set similarity and biological similarity to assess compound specificity.

The expected results should be relevant for basic researchers, clinical scientists and drug development specialists.