Benutzerspezifische Werkzeuge

Objectives/Aims

The aim of this project is to identify the role of Shh in the regulation of adult adrenocortical function and disease. Specifically, we will examine its influence on normal proliferation, hyperplasia and tumour formation, as well as its function in modulation of steroidogenesis.

(I) Determine the role of Shh in adrenal cell proliferation, hyperplasia and tumour formation.

We will asses the expression of Shh pathway components in the adult mouse adrenal gland as well as in normal human adrenal gland, hyperplasia and adrenal tumours. Furthermore, we will determine the exact localisation of the Shh components within the adrenal gland and evaluate whether Shh pathway activation is required for adrenal cells proliferation, hyperplasia and tumour formation.

If activation of Hh signalling induces tumourigenesis, it is possible that adrenal tumours have activating mutations in components of the Hh pathway. Therefore, the presence of mutations in Hh components will be investigated in adrenal tumours.

(II) Assess the role of Shh in adrenal steroid hormone production.

We observed in preliminary studies that Shh directly increases aldosterone and cortisol secretion from the adrenocortical cell line NCI-H295R, whereas no effect on DHEA secretion was observed. Furthermore, lipoproteins strongly strengthened the effect of Shh on steroidogenesis. We will now investigate in details how Shh per se and how binding of Shh to lipoproteins modulate steroidogenesis. We will further investigate the relevance of this data in vivo.

(III) Assess the role of Shh in adrenal dysfunction related to metabolic diseases and stress-associated conditions.

Stress-associated diseases are accompanied by adrenal gland dysfunction. We hypothesise that the Shh pathway is required for proper adrenal gland function. Therefore, we will analyze the role of Shh in systemic diseases associated with severe adrenal dysfunction such as systemic inflammatory response syndrome (SIRS).

Considering the synergism between lipoproteins and Shh in the modulation of steroidogenesis, we will investigate the role of Shh in metabolic diseases associated with disturbed lipid metabolism including metabolic syndrome and cachexia.