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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=661484
• 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.

哺乳动物膳食铁吸收和体内铁运输受肝源性肽激素铁调素控制。铁调素与靶细胞中的铁输出蛋白ferroportin结合并促进其降解，从而抑制铁流入血流。铁调素的表达需要血幼素（hemojuvelin，HSP 70），一种骨形态发生蛋白（BMP）共受体。阻碍通过增强铁依赖性BMP/SMAD信号传导至肝中的铁调素（铁调素产生的主要部位）来起作用。肝特异性铁调素或铁调素的破坏导致严重的铁过载。hepcidin和hepcidin也在其他组织中表达，在那里它们可以发挥局部功能。心脏和骨骼肌中有大量的阻碍物。通过产生肝脏和肌肉特异性HSP 70-/-小鼠，我们证明了只有肝脏HSP 70调节全身铁稳态。该提案的目的是表征心脏和骨骼肌中的Heptase功能。在初步的数据中，我们提供的证据表明，心脏抑制剂作为一个抑制剂（而不是增强剂）的本地hepcidin的表达。我们还表明，骨骼肌免于铁过载HSP 70-/-小鼠。我们推测心脏HPLCs对心脏铁代谢的控制至关重要，尤其是在缺氧条件下，而骨骼肌HPLCs在组织修复中表现出铁非依赖性功能。为了解决这些假设，我们将与培养的心肌细胞进行生化研究，并在组织特异性HLA-B-/-小鼠的心脏铁代谢的特点。此外，我们还将研究在生理条件下或缺氧条件下，Hisp和hepcidin在心脏铁代谢和功能中的作用。最后，我们将探讨HSP 70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，并得到了初步数据的支持。我们正在采取生物化学、生理学和遗传学方法。关键的试剂和工具都在手中。我们的实验室是唯一一个拥有肌肉特异性HSP 70-/-小鼠与心脏中断HSP 70，这使我们在一个独特的位置，以完成拟议的工作。该项目的实施将为心脏和骨骼肌中的HALGOR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尚未探索。