Identification of iron-related signals controlling BMP expression in liver non-parenchymal cells

全身性铁稳态的控制演变为维持血浆铁浓度，以确保组织和细胞的充足供应，同时防止器官铁超载。小的肝细胞衍生的多肽激素海普西丁同步全身铁通量，以控制循环中可用于细胞铁摄取的铁量(例如，在骨细胞中)。海普西丁以铁出口蛋白铁蛋白为靶标，触发其降解，从而阻止饮食中铁的吸收和巨噬细胞铁的释放。铁生物学中的一个基本问题仍然没有答案：肝脏是如何感知铁的水平的？肝细胞中海普西丁的表达受BMP/SMAD信号通路的控制，通过该通路，BMP在肝脏非实质细胞中表达，以响应全身铁水平的变化。我们推测，几种肝细胞类型(肝细胞、LSECs、星状细胞和Kupffer细胞)的相互作用将在海普西丁对铁的反应中发挥作用。通过分析全身性铁过载和缺铁的小鼠遗传模型，我们将确定所有肝细胞类型的基因反应模式，并在原代细胞(Co)培养中识别和验证BMP对铁的反应所涉及的途径。此外，我们将测试在肝脏中识别的信号和通路是否也将在骨骼中发挥作用，以调节BMP水平。

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 unanswered: 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. We hypothesize that a cross-talk of several liver cell types (hepatocytes, LSECs, stellate cells and Kupffer cells) will play a role for the hepcidin response to iron. By analyzing genetic mouse models of systemic iron overload and deficiency we will determine gene response patterns in all liver cell types and identify and validate pathways involved in the responses of BMPs to iron in primary cell (co) cultures. Additionally, we will test whether signals and pathways identified in the liver will also be operational in the bone for regulation of BMP levels.