“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.

铁是许多代谢过程所需的辅因子，但过量存在时是有毒的，铁代谢的不平衡是一些最常见的疾病的原因。在过去的二十年里，广泛的研究已经发现了铁稳态的关键分子。在这些分子中，跨膜质子偶联的铁输入者DMT 1（二价金属转运蛋白1）被证明是必不可少的膳食铁同化，以及铁收购红细胞。为了防止铁缺乏和过量，必须非常严格地控制DMT 1的表达。在哺乳动物中，细胞铁稳态由铁调节蛋白（IRP）-1和-2协调，其通过与称为铁响应元件（IRE）的顺式调节RNA结构结合来控制铁代谢mRNA的命运。DMT 1 mRNA在其3'非翻译区携带单个非典型IRE，因此可能受IRP调控。然而，缺乏足够的动物模型，到目前为止，阻碍了更好地理解DMT 1 IRE的体内功能。为了填补这一空白，我们已经建立了一种选择性破坏DMT 1的3 'IRE的小鼠系，这代表了第一个具有这种RNA基序的靶向诱变的动物模型。我们的初步工作表明，IRE的DMT 1是所需的正常红细胞生成，并防止系统性铁过载在年轻的成年小鼠保持在标准的实验室条件。基于组织和血清学铁代谢参数的详细探索，血液学参数的研究，和铁代谢基因的分子分析，我们建议确定在年轻的成年DMT 1突变小鼠中观察到的铁失衡的原因。此外，我们还将研究与不同铁代谢特征相关的其他生命阶段的铁表型，更准确地说，是在围产期，小鼠对铁的需求量很高，依赖母乳，以及在铁储存量很高，饮食正常的老年动物中。此外，我们将评估DMT 1的IRE是否以及如何影响铁稳态机制对膳食铁可用性波动和应激红细胞生成条件的适应性反应。通过这项工作，我们希望揭示细胞中一种重要的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调控中的作用的理解。