Project A02

The systemic influence of adrenal hypoxia pathway proteins: from physiological functions to pathological alterations

During the first two funding periods, we made a decisive contribution to understanding the previously insufficiently characterized role of hypoxia in adrenal gland function. Using unique transgenic mouse models developed within the SFB/TRR 205, we were able to show for the first time that hypoxia-inducible factor 1α (HIF1α) is a central regulator of adrenocortical steroidogenesis in vivo. In addition, we identified a HIF1α-dependent network of hypoxia-regulated microRNAs that specifically modulates steroidogenic enzymes during acute hypoxia. Our work also demonstrates that a chronic, HIF1α-mediated increase in endogenous glucocorticoids has profound effects on the hematopoietic system. These include altered stem cell quiescence, self-renewal, and lymphoid differentiation. These effects are strictly dependent on the glucocorticoid receptor (GR) in hematopoietic cells.

Building on these findings, Project A02 in the third funding period focuses on the systemic translation of these changes with three closely related objectives.

(I) Characterization of the vascular instability in the intestine mediated by the adrenal HIF1α-glucocorticoid axis and its contribution to local and systemic inflammatory reactions, including joint involvement.

(II) Analysis of the role of the hematopoietic and endothelial glucocorticoid GR axis in the regulation of dermal immunity and skin integrity, particularly in the context of delayed wound healing and altered myeloid cell dynamics.

(III) Investigation of the effects of HIF-controlled steroidogenesis on the cardiovascular system and the development of cardiovascular diseases. The central tools for this are our adrenocortical HIF transgenic mouse lines and GR-deficient models.

Overall, A02 aims to elucidate the role of hypoxia-dependent signaling in the adrenal gland as a systemic regulator of pathophysiological processes in vivo and to identify new targets for therapeutic strategies in glucocorticoid-associated diseases.

© SFB/TRR 205