Molecular Synergism between Hormonal Signaling and Iron Homeostasis

• Applicant: Professorin Maja Vujic Spasic, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2012 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 222169677

Systemic iron homeostasis is disrupted in the common, potentially fatal iron overload disorder, hereditary hemochromatosis (HH). HH is hallmarked by increased serum iron levels and tissue iron deposition which leads to multiple organ failure/dysfunction if the disease remains untreated. The most prevalent form of HH is caused by mutations in the Hfe gene. We recently demonstrated that Hfe acts in hepatocytes to maintain systemic iron levels and to control expression of the systemic iron regulator hepcidin, clarifying a long-standing question in medicine. Beyond its essential role in hepatocytes, we propose that Hfe expression in cells other than hepatocytes is critical to maintain tissue-specific iron homeostasis. Here we demonstrate an unexpected action of Hfe in macrophages and propose that macrophage-Hfe functions are required to control tissue iron homeostasis and hepatic hepcidin expression during inflammation. Moreover, we identify glucocorticoids as novel regulators of iron homeostasis thus paving the way towards the discovery of molecular synergism between hormonal and iron homeostasis. We expect to foster our understanding of fundamental molecular mechanisms involved in the maintenance of body iron homeostasis and to uncover the intimate link between iron and hormonal signalling.

• DFG Programme: Research Grants