Function of hemojuvelin in the heart and skeletal muscles

哺乳动物饮食中铁的吸收和体内铁的运输受肝源性多肽激素海普西丁的控制。海普西丁与靶细胞中铁出口蛋白铁蛋白结合，促进其降解，从而抑制进入血流的铁通量。海普西丁的表达需要血凝素(hemjuvelin，Hjv)，一种骨形态发生蛋白(BMP)的共同受体。HJV通过增强铁依赖的BMP/SMAD信号转导肝脏中的海普西丁来发挥作用，肝脏是海普西丁产生的主要部位。肝脏特异性干扰海普西丁或Hjv会导致严重的铁超载。海普西丁和Hjv在其他组织中也有表达，在这些组织中它们可能发挥局部功能。HJV在心脏和骨骼肌中含量非常丰富。通过产生肝脏和肌肉特异的Hjv-/-小鼠，我们证明只有肝脏Hjv调节全身铁平衡。*这项建议的目标是表征Hjv在心脏和骨骼肌中的功能。在初步数据中，我们提供了证据表明，心脏Hjv对局部海普西丁的表达起到抑制(而不是增强)的作用。我们还发现，在Hjv-/-小鼠中，骨骼肌不受铁超载的影响。*我们假设，心脏Hjv对心脏铁代谢的控制至关重要，特别是在低氧条件下，而骨骼肌Hjv在组织修复中表现出铁不依赖的功能。为了解决这些假设，我们将对培养的心肌细胞进行生化研究，并表征组织特异性Hjv-/-小鼠的心肌铁代谢。此外，我们还将研究在生理条件或低氧条件下，Hjv和海普西丁在心脏铁代谢和功能中的作用。最后，我们将探索Hjv在损伤后骨骼肌再生中的可能作用。*该提议建立在我们先前工作的基础上，并得到了初步数据的支持。我们正在进行生化、生理和遗传方面的研究。关键试剂和工具已在手中。我们的实验室是唯一拥有肌肉特异性Hjv-/-小鼠的实验室，这些小鼠患有Hjv心脏中断，这使我们处于完成拟议工作的独特位置。该项目的实施将为Hjv在心脏和骨骼肌中的生化和生理功能提供重要的见解，这些功能在很大程度上是未知的。

Mammalian dietary iron absorption and body iron traffic are controlled by hepcidin, a liver-derived peptide hormone. Hepcidin binds to the iron exporter ferroportin in target cells and promotes its degradation, thereby inhibiting iron flux into the bloodstream. The expression of hepcidin requires hemojuvelin (Hjv), a bone morphogenetic protein (BMP) co-receptor. Hjv operates by enhancing iron-dependent BMP/SMAD signaling to hepcidin in the liver, the major site of hepcidin production. Liver-specific disruption of either hepcidin or Hjv leads to severe iron overload. Both hepcidin and Hjv are also expressed in other tissues, where they may exert localized functions. Hjv is highly abundant in the heart and skeletal muscles. By generating liver- and muscle-specific Hjv-/- mice, we demonstrated that only liver Hjv regulates systemic iron homeostasis.***The objective of this proposal is to characterize the function of Hjv in the heart and skeletal muscles. In preliminary data we provide evidence that cardiac Hjv acts as a suppressor (rather than enhancer) of local hepcidin expression. We also show that skeletal muscles are spared from iron overload in Hjv-/- mice.***We hypothesize that cardiac Hjv is crucial for the control of heart iron metabolism especially under hypoxia, while skeletal muscle Hjv exhibits an iron-independent function in tissue repair. To address these hypotheses, we will perform biochemical studies with cultured cardiomyocytes, and characterize cardiac iron metabolism in tissue-specific Hjv-/- mice. Moreover, we will investigate the roles of Hjv and hepcidin in cardiac iron metabolism and function under physiological conditions or under hypoxia. Finally, we will explore a possible role of Hjv in skeletal muscle regeneration following injury.***The proposal builds on our previous work and is supported by preliminary data. We are undertaking biochemical, physiological and genetic approaches. Critical reagents and tools are in hand. Our laboratory is the only one possessing muscle-specific Hjv-/- mice with cardiac disruption of Hjv, which places us in a unique position to accomplish the proposed work. Implementation of this project will provide important insights on the biochemical and physiological functions of Hjv in the heart and in skeletal muscles, which are largely unexplored.