The role of hemojuvelin in the regulation of iron metabolism

描述(申请人提供)：铁超负荷疾病是世界上最常见的遗传性疾病之一。这项建议分析了导致铁过载疾病的分子途径，包括遗传性血色素沉着症。最近的发现为了解铁代谢和铁超载疾病的基本分子创造了新的机会。多肽荷尔蒙海普西丁成为全身铁稳态的主要调节者。体内的炎症和铁负荷诱导了海普西丁的合成，而缺氧和贫血则抑制了海普西丁的合成。反过来，海普西丁抑制肠道对膳食铁的吸收，以及巨噬细胞对铁的循环和肝脏储存的铁释放。海普西丁缺乏和由此导致的铁吸收失调是大多数遗传性血色病的共同致病特征，除了那些由海普西丁靶基因突变引起的血色素沉着症。感知铁和调节海普西丁合成的分子通路对铁负荷的反应尚不清楚。血色素沉着症中的特定基因突变是如何导致海普西丁缺乏症的，目前也不清楚。我们推测，血色沉着症基因HFE、转铁蛋白受体2和血凝素基因的纯合破坏会导致海普西丁的部分或完全缺乏，它们编码的蛋白质调节海普西丁的产生。在这些基因中，血凝素似乎是与海普西丁“最接近”的基因，因为它的纯合子破坏导致了海普西丁的缺失或几乎缺失。此外，血凝素的破坏是青少年血色沉着症的主要原因，表型完全模仿海普西丁基因本身的纯合子破坏。此外，血凝素属于一个受体配体家族，即斥力引导分子(RGM)，这表明它可能在信号转导途径中发挥作用。通过专注于血凝素并确定其合作伙伴和功能，这项R21提案将为理解铁如何调节海普西丁的生产奠定基础。具体地说，我们将：1.制备和鉴定人血凝素，并产生抗血凝素抗体。2.鉴定血凝素受体(S)。3.分析铁和炎症对血凝素合成和加工的调节4.鉴定血凝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提案的基础，以阐明铁负荷是如何被感知的，以及它是如何调节海普西丁的产生的，这些过程构成了铁吸收和运输的系统调控的传入弧线。

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.