The role of hemojuvelin in the regulation of iron metabolism

描述（由申请人提供）：铁超载疾病是世界上最常见的遗传性疾病之一。这项提案分析了导致铁超载疾病的分子途径，包括遗传性血色病。最近的发现为铁代谢和铁超载疾病的基本分子理解创造了新的机会。肽激素铁调素作为系统性铁稳态的主要调节剂出现。铁调素合成由炎症和体内铁负荷诱导，并被缺氧和贫血抑制。反过来，铁调素抑制膳食铁的肠吸收，以及巨噬细胞的铁再循环和肝脏储存的铁释放。铁调素缺乏和由此导致的铁吸收失调是大多数遗传性血色素沉着症的共同发病特征，除了由铁调素靶点ferroportin突变引起的那些。感知铁和调节铁调素合成以响应铁负载的分子途径尚不清楚。目前还不清楚血色素沉着症中突变的特定基因如何导致铁调素缺乏症。我们的理由是，血色素沉着病基因HFE，转铁蛋白受体2和hemojuvelin，其纯合破坏导致部分或完全缺乏铁调素，编码的蛋白质，调节铁调素的生产。在这些基因中，hemojuvelin似乎是“最接近”铁调素，因为其纯合破坏导致铁调素的缺失或几乎缺失。此外，hemojuvelin的破坏是青少年血色素沉着症的主要原因，并且在表型上完全模仿铁调素基因本身的纯合破坏。此外，hemojuvelin属于受体配体家族，排斥导向分子（RGM），表明它可能在信号转导途径中发挥作用。通过关注hemojuvelin并确定其合作伙伴和功能，这项R21提案将为了解铁如何调节hepcidin的产生奠定基础。具体来说，我们将：1。制备和表征人血幼素并产生抗血幼素抗体。2.鉴别血幼素受体。3.分析铁和炎症对血幼素合成和加工的调节。确定血幼素在体内的生物学效应。这项工作的结果将形成一个全面的R01建议的基础，以阐明铁负荷是如何感知的，以及它是如何调节铁调素的生产，这些过程构成了铁吸收和运输的系统调节的传入弧。

DESCRIPTION (provided by applicant): Iron overload diseases are among the most common genetic disorders worldwide. This proposal analyzes the molecular pathways that lead to iron overload diseases, including hereditary hemochromatosis. Recent discoveries created new opportunities for fundamental molecular understanding of iron metabolism and the diseases of iron overload. The peptide hormone hepcidin emerged as the principal regulator of systemic iron homeostasis. Hepcidin synthesis is induced by inflammation and by iron loading in vivo, and is suppressed by hypoxia and anemia. In turn, hepcidin inhibits the intestinal absorption of dietary iron, as well as iron recycling by macrophages and iron release from hepatic stores. Hepcidin deficiency and the resulting dysregulation of iron absorption are the common pathogenetic features of most hereditary hemochromatoses, except for those caused by mutations in the hepcidin target, ferroportin. The molecular pathways that sense iron and regulate hepcidin synthesis in response to iron loading are not known. It is also not clear how the specific genes mutated in hemochromatosis cause hepcidin deficiency. We reason that the hemochromatosis genes HFE, transferrin receptor 2 and hemojuvelin, whose homozygous disruption causes partial or complete deficiency of hepcidin, encode proteins that regulate hepcidin production. Of these genes, hemojuvelin appears to be the "closest" to hepcidin because its homozygous disruption causes the absence or near absence of hepcidin. Moreover, the disruption of hemojuvelin is the main cause of juvenile hemochromatosis, and phenotypically completely mimics homozygous disruption of the hepcidin gene itself. Furthermore, hemojuvelin belongs to a family of receptor ligands, repulsive guidance molecules (RGM), indicating that it may function in a signal transduction pathway. By focusing on hemojuvelin and identifying its partners and function, this R21 proposal will lay the groundwork for understanding how iron regulates hepcidin production. Specifically, we will: 1. Prepare and characterize human hemojuvelin and generate anti-hemojuvelin antibodies. 2. Identify the hemojuvelin receptor(s). 3. Analyze the regulation of hemojuvelin synthesis and processing by iron and inflammation 4. Identify the biological effects of hemojuvelin in vivo. The results of this work will form the foundation of a comprehensive R01 proposal to elucidate how iron load is sensed and how it regulates hepcidin production, processes that constitute the afferent arc of systemic regulation of iron absorption and transport.