TMPRSS6-mediated regulation of iron via cleavage of components of the bone morphogenetic protein signaling pathway in liver and bone

TMPRSS6 通过裂解肝脏和骨中骨形态发生蛋白信号通路的成分介导铁的调节

• 批准号: 448946841
• 负责人: Professor Dr. Guiscard Seebohm
• 金额: --
• 依托单位: Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/448946841?language=en
• 关键词: TMPRSS6; mediated; regulation; iron; via

The regulation of iron is crucial for liver and bone homeostasis. The transmembrane serine protease 6 (TMPRSS6) interacts with multiple components of the bone morphogenetic protein (BMP) signaling pathway including the BMP type I receptors ALK2 and ALK3, and thereby reduces the expression of the iron regulatory hormone hepcidin. Physiologically, hepcidin binds to and inactivates the iron exporter ferroportin if serum iron levels have reached sufficient levels. The loss of function mutation in TMPRSS6 causes iron-resistant-iron deficient anemia due to inappropriately high hepcidin levels. Even though aspects of TMPRSS6 binding and function in systemic iron homeostasis and liver regulation have been investigated, a detailed understanding of this regulatory system is elusive. The overall aim of this project is to investigate in depth signaling mechanisms and binding of TMPRSS6. Therefore, we will focus on the three main goals: 1) in silico-modeling of TMPRSS6 interactions with BMP receptors and the iron regulatory proteins Hfe, Hjv, Tfr1 and Tfr2, 2) investigation of TMPRSS6 interactions with components of the BMP signaling pathway and other iron regulatory proteins in vivo in mouse models, and 3) assessing the importance of TMPRSS6 in bone cells. In addition, we will investigate whether changes of systemic iron homeostasis impair the signaling mechanisms, which contributing factors occur, and how activation or blockage affects binding and receptor formation. This proposal will unravel mechanisms of TMPRSS6 actions in liver, iron sensing, and bone.

铁的调节对于肝脏和骨的稳态是至关重要的。跨膜丝氨酸蛋白酶6（TMPRSS 6）与骨形态发生蛋白（BMP）信号传导途径的多种组分（包括BMP I型受体ALK 2和ALK 3）相互作用，从而降低铁调节激素铁调素的表达。在生理上，如果血清铁水平达到足够的水平，铁调素结合并灭活铁输出体膜铁转运蛋白。TMPRSS 6中的功能缺失突变由于不适当的高铁调素水平而导致铁抗性-缺铁性贫血。尽管已经研究了TMPRSS 6结合和在系统性铁稳态和肝脏调节中的功能方面，但是对该调节系统的详细理解是难以捉摸的。本项目的总体目标是深入研究TMPRSS 6的信号传导机制和结合。因此，我们将重点关注三个主要目标：1）TMPRSS 6与BMP受体和铁调节蛋白Hfe、Hjv、Tfr 1和Tfr 2的相互作用的计算机模拟，2）研究TMPRSS 6与BMP信号通路组分的相互作用和其他铁调节蛋白在小鼠模型中的体内作用，以及3）评估TMPRSS 6在骨细胞中的重要性。此外，我们还将研究系统性铁稳态的变化是否会损害信号传导机制，哪些因素会起作用，以及激活或阻断如何影响结合和受体形成。该提案将揭示TMPRSS 6在肝脏，铁传感和骨骼中的作用机制。