Project Details
Projekt
Identification of iron-related signals controlling BMP expression in liver non-parenchymal cells
Applicant
Professorin Dr. Martina Muckenthaler
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Control of systemic iron homeostasis evolved to maintain a plasma iron concentration that secures adequate supplies to tissues and cells while preventing organ iron overload. The small hepatocyte-derived peptide hormone hepcidin synchronizes systemic iron fluxes to control the amount of iron available in the circulation for cellular iron uptake (e.g. in bone cells). Hepcidin targets the iron export protein ferroportin to trigger its degradation, thus preventing dietary iron absorption and macrophage iron release. A fundamental question in iron biology still remains to be addressed: how are iron levels sensed by the liver? Hepcidin mRNA expression in hepatocytes is controlled by the BMP/SMAD signaling pathway, whereby BMPs are expressed in liver non-parenchymal cells in response to changes in systemic iron levels. In the last funding period we filled important gaps in our understanding of hepcidin control and established that iron-dependent BMP6 responses in liver sinusoidal endothelial cells (LSECs) require a protein secreted from hepatocytes. By applying multi-approach strategies, we will now aim to identify the hepatocyte-derived protein critical for iron-dependent BMP6 activation. We will generate Bmp6ScarLuc mice to increase the throughput of our experiments and to detect Bmp6 modulations in a time-resolved manner. In addition, by introducing the hepcidin-resistant ferroportin allele (FPNC326S) into murine LSECs and hepatocytes we will dissect the role of the cellular iron status for BMP6 control in vivo. Finally, we will identify the signaling pathways that mediate iron-dependent BMP6 responses in LSECs and their cross-talk to inflammation and oxidative stress. With this experimental approach we expect to gain detailed insight into how LSECs control BMP6 responses to ultimately determine systemic iron availability that is crucial for organ functions, including bone health.
DFG Programme
Research Units
