Project Details
Projekt
4-“T”-interplay (Type I BMP Receptors/TFR1/TFR2/TMPRSS6) in iron sensing and bone homeostasis.
Subject Area
Endocrinology, Diabetology, Metabolism
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 436298031
The goal of this proposal is to investigate the interplay of the 4 “T”s: the transmembrane serine protease 6 (TMPRSS6), transferrin receptor 1 (TFR1) and transferrin receptor 2 (TFR2) with the type I-bone morphogenetic protein receptors ALK2 and ALK3 in iron sensing and bone homeostasis. Structural modeling revealed interactions of TMPRSS6 with ALK2 and ALK3. Double hepatocyte specific Alk2/Tmprss6 deficient mice were generated and presented a phenotype similar to the iron overloaded hepatocyte-specific Alk2 deficiency, suggesting signaling of TMPRSS6 via ALK2. In addition, the interaction of the iron regulatory protein hemojuvelin with ALK2 and ALK3 was identified (Dogan et al., 2024). In our follow-up grant application, the overall goal is to increase the knowledge of the interplay of TMPRSS6, TFR1 and TFR2 with BMP signaling. We hypothesize that TMPRSS6, TFR2 and the bone morphogenetic protein receptors type I interact with each other to regulate iron homeostasis and that BMP type I receptors are essential for TMPRSS6, TFR1 and TFR2 to mediate their effect of iron increase and hepcidin modulation. We will generate the hepatocyte specific Tmprss6/Alk3 double knockout mouse to elucidate, if TMPRSS6 requires ALK3 for signaling. Second, the role of hepatic TFR1 in systemic iron homeostasis will be investigated by structural modeling in vitro as well as in hepatocyte specific Alk3 and Alk2 deficient mice by TFR1 overexpression in vivo. Third, we will elucidate the regulatory role of TFR2 in BMP signaling and hepcidin expression. TFR2 will be overexpressed in hepatocyte-specific Alk2, Alk3 and fourth, in Tmprss6 knockout mice to investigate the dependence of the 4 “T”s: TFR2, TFR1,TMPRSS6 and the type I BMP receptors ALK2 and ALK3. Bone analyses and proteomic analyses will be performed in all experiments (with TP3 and TP7).
DFG Programme
Research Units
