“Regulation of iron metabolism: Deciphering the biological functions of the iron responsive element of divalent-metal transporter 1”

“铁代谢的调节：破译二价金属转运蛋白 1 铁反应元件的生物学功能”

• 批准号: 402801855
• 负责人: Dr. Bruno Galy, Ph.D.
• 金额: --
• 依托单位: Abteilung Virus-assoziierte Karzinogenese
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/402801855?language=en
• 关键词: Regulation; iron; metabolism; Deciphering; biological

Iron is a co-factor required for numerous metabolic processes but toxic when present in excess, and imbalances of iron metabolism account for some of the most common diseases. Extensive research during the last two decades has uncovered key molecules of iron homeostasis. Among those molecules, the transmembrane proton-coupled iron importer DMT1 (divalent metal transporter 1) was shown to be essential for dietary iron assimilation as well as for iron acquisition by erythroid cells. To prevent both iron insufficiency and excess, the expression of DMT1 must be controlled very tightly. In mammals, cellular iron homeostasis is orchestrated by the iron regulatory proteins (IRP)-1 and -2, which control the fate of iron metabolism mRNAs by binding to cis-regulatory RNA structures named iron-responsive elements (IRE). The DMT1 mRNA bears a single, non-canonical IRE in its 3’ untranslated region, and is thus potentially regulated by the IRPs. However, the lack of adequate animal models has so far hampered a better comprehension of the in vivo functions of the DMT1 IRE. To fill this gap, we have created a mouse line with selective disruption of the 3’IRE of DMT1, which represents the first animal model with targeted mutagenesis of such RNA motifs. Our preliminary work indicates that the IRE of DMT1 is required for normal erythropoiesis and to prevent systemic iron overload in young adult mice maintained under standard laboratory conditions. Based on a detailed exploration of tissular and serological iron metabolism parameters, a study of hematological parameters, and a molecular analysis of iron metabolism genes, we propose to determine the cause of the iron imbalance observed in young adult DMT1-mutant mice. In addition, we will examine the iron phenotype at other stages of life asociated with distinct iron metabolism characteristics, more precisely during perinatal life when mice have high iron needs and rely on maternal milk, and in aged animals with high iron stores and feeding on a normal diet. Furthermore, we will assess whether and how the IRE of DMT1 impacts on the adaptative responses of the iron homeostasis machinery to fluctuations in dietary iron availability and in conditions of stress erythropoiesis. With this work we wish to unveil new facets of an essential iron transporter in the cell, and enhance our understanding of the role of posttranscriptional control mechanisms in metabolic regulations.

铁是众多代谢过程所需的共同因素，但在过量时有毒，铁代谢的失衡造成了一些最常见的疾病。在过去的二十年中，广泛的研究发现了铁稳态的关键分子。在这些分子中，传输神经质子偶联的铁进口剂DMT1（二价金属转运蛋白1）被证明对于饮食中的铁同化以及红细胞细胞采集铁是必不可少的。为了防止铁不足且超过超过，必须密切控制DMT1的表达。在哺乳动物中，细胞铁稳态由铁调节蛋白（IRP）-1和-2策划，这些蛋白质（IRP）-1和-2通过与CIS调控RNA结构（称为铁反应性元素（IRE））结合来控制铁代谢mRNA的命运。 DMT1 mRNA在其3'未翻译区域中带有单个非典型的IRE，因此可能受IRP的调节。但是，到目前为止，缺乏足够的动物模型阻碍了人们对DMT1 IRE的体内功能的更好理解。为了填补这一空白，我们创建了一条小鼠线，并选择性破坏了DMT1的3'IRE，这代表了第一个具有此类RNA基序的靶向诱变的动物模型。我们的初步工作表明，正常的红细胞生成需要DMT1的IRE，并防止年轻小鼠的全身铁超负荷，以保持了解标准实验室状况。基于对钛和血清学铁代谢参数的详细探索，血液学参数的研究以及对铁代谢基因的分子分析，我们建议确定年轻成人DMT1突变小鼠中观察到的铁不平衡的原因。此外，我们将在与不同的铁代谢特征相关的其他生活阶段进行铁表型，更确切地说，在围产期生命中，当小鼠有高铁需求并依靠母乳，以及具有高铁储存的老年动物，并以正常的饮食为食。此外，我们将评估DMT1的IRE是否以及如何影响铁稳态机制对饮食铁的可用性波动和压力红细胞生成的条件的自适应反应。通过这项工作，我们希望揭示细胞中必需铁转运蛋白的新方面，并增强我们对转录后控制机制在代谢法规中的作用的理解。