Gaining New Insights Into Regulation of Systemic Iron Homeostasis.

• Applicant: Professorin Dr. Andrea Ulrike Steinbicker
• Subject Area: Anaesthesiology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 256183843

Iron is required for erythropoiesis. Precise control of the hepatic hormone hepcidin, the central iron regulator in the body, is important for regulation of systemic iron homeostasis in order to maintain a balance between iron demand and supply. Hepcidin expression is stimulated by iron or inflammation, and leads to degradation and internalization of the iron export channel. Then, iron cannot be absorbed in the intestine, and remains trapped in the iron stores, such as hepatocytes and macrophages. An induction of hepcidin causes the anemia of chronic disease (ACD). A relative or absolute deficiency of hepcidin causes iron overload, also called hemochromatosis. Both diseases are highly prevalent and do have a severe impact on patient`s health. Therefore, the overall goal of the first proposal and of this renewal proposal is to increase our knowledge in systemic iron regulation in order to be able to develop treatments for diseases caused by imbalances of hepcidin regulation. A way to decrease hepcidin expression by inflammation is inhibition of the bone morphogenetic protein (BMP) signaling pathway, which cures ACD in mice. In addition, mice with a deficiency of a BMP receptor present with hepcidin deficiency and iron overload.In the first grant, the BMP receptor critical for the pathogenesis of ACD was investigated, the protein-protein interactions required for BMP type I receptors ALK2- and ALK3-dependent iron regulation were determined in vitro and the role of ALK2 and ALK3 in regulation of hepatic iron metabolism and iron overload were characterized. Our data indicate that hepcidin induction relies not only on BMP receptors but also on other regulatory proteins, as the BMP type I receptor ALK3 interacts with the iron regulatory proteins HFE and TfR2 in vitro. Therefore, protein-protein interactions will be investigated in vivo in specific aim 1 of the renewal grant proposal. Gene overexpression using adeno-associated viruses in mice with and without hepatocyte-specific Alk3 deficiency will be used to proof relevant interactions and their functions in vivo. In specific aim 2, murine iron overload of the established murine iron overload models will be imaged by small animal MRI to determine iron accumulation at organ level as well as µXRF and LS-MCPM to determine iron accumulation at single cell level. In specific aim 3 we will investigate murine cardiac iron overload undergoing either ischemia/reperfusion injury, transaortic elongation or exposed to cardiotoxic drugs in order to learn about the pathophysiologic development of iron-dependent cardiomyopathy and to treat the disease.The renewal grant will enable us to gain novel insights into regulation of systemic iron homeostasis, which will be of high impact to the research society and all the physicians caring for patients with diseases caused by imbalances of the iron regulatory system.

• DFG Programme: Research Grants