Function of hemojuvelin in the heart and skeletal muscles

血幼素在心脏和骨骼肌中的功能

• 批准号: RGPIN-2017-05406
• 负责人: Pantopoulos, Konstantinos
• 金额: $ 1.89万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=681500
• 关键词: Function; hemojuvelin; heart; skeletal; muscles

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.

哺乳动物膳食铁的吸收和体内铁的运输是由一种肝脏来源的肽激素hepcidin控制的。Hepcidin与靶细胞中的铁输出蛋白铁转运蛋白结合并促进其降解，从而抑制铁流入血液。hepcidin的表达需要血幼蛋白（Hjv），一种骨形态发生蛋白（BMP）共受体。Hjv通过增强铁依赖性BMP/SMAD信号传导到肝脏中的hepcidin，而肝脏是hepcidin产生的主要部位。肝脏特异性hepcidin或Hjv的破坏会导致严重的铁超载。hepcidin和Hjv也在其他组织中表达，在那里它们可能发挥局部功能。Hjv在心脏和骨骼肌中含量丰富。通过产生肝脏和肌肉特异性Hjv-/-小鼠，我们证明只有肝脏Hjv调节全身铁稳态。***本提案的目的是表征Hjv在心脏和骨骼肌中的功能。在初步数据中，我们提供证据表明心脏Hjv作为局部hepcidin表达的抑制因子（而不是增强因子）。我们还发现Hjv-/-小鼠骨骼肌免于铁超载。***我们假设心脏Hjv对心脏铁代谢的控制至关重要，特别是在缺氧情况下，而骨骼肌Hjv在组织修复中表现出不依赖铁的功能。为了解决这些假设，我们将在培养的心肌细胞中进行生化研究，并在组织特异性Hjv-/-小鼠中表征心脏铁代谢。此外，我们将探讨Hjv和hepcidin在生理条件和缺氧条件下心脏铁代谢和功能中的作用。最后，我们将探讨Hjv在损伤后骨骼肌再生中的可能作用。该建议建立在我们以前的工作基础上，并得到初步数据的支持。我们正在进行生物化学、生理学和遗传学的研究。关键的试剂和工具已经准备好了。我们的实验室是唯一一个拥有Hjv心脏中断的肌肉特异性Hjv-/-小鼠的实验室，这使我们处于一个独特的位置来完成拟议的工作。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，这在很大程度上是未知的。