Project Details
Projekt
Unraveling mechanisms regulating the dynamics of BMP signal transduction and its impact on hepcidin expression with a systems biology approach
Applicant
Professorin Dr. Ursula Klingmüller
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
Hepatocytes are the major cells for iron storage and secrete the iron regulator hepcidin. Expression of hepcidin is induced by the bone morphogenetic protein (BMP)/Smad signaling pathway. Transferrin receptor 2 (Tfr2) binds BMP ligands and BMP receptors, and activates Smad signaling, whereas the transmembrane serine protease 6 (TMPRSS6) cleaves BMP receptors and decreases BMP signal transduction. Additionally, hepcidin is an acute phase protein that is induced by interleukin (IL-)6 via the JAK1-STAT3 pathway. It was suggested that the IL-6/STAT and BMP/Smad axes interact at the transcription factor level, but the impact of this cross-talk on the dynamics of BMP signaling and on hepcidin expression in hepatocytes remains to be mechanistically resolved. To disentangle such complex interrelations, we will use a systems biology approach. With this approach we identified the three most relevant Smad complexes and predicted their impact on target gene expression. Based on a mathematical model of the IL-6/STAT3 signaling pathway, we predicted optimal inhibitor dosing to modulate the acute phase response including hepcidin expression. In our project we will address the communication between bone cells and hepatocytes ensuring iron homeostasis. By a mass spectrometric approach we will quantify the dynamics of plasma factors in response to iron overload in mouse models. Utilizing our integrative mathematical model of IL-6/BMP signal transduction and a targeted mass spectrometry approach, we will elucidate the impact of Tfr2 and of TMPRSS6 on the dynamics of hepcidin expression and will identify mechanisms regulating hepcidin expression that are altered in chronic liver diseases. The integrative approach that quantitatively dissects the communication between bone and liver and the regulation of iron homeostasis promises to identify novel strategies to prevent iron overload.
DFG Programme
Research Units
