Biological Function of Iron Responsive Elements

描述（由申请人提供）：此申请是对NOT-OD-09-058的回应，“NIH宣布为竞争性修订申请提供恢复法案资金。”由父母资助的研究解决了哺乳动物体内铁稳态如何调节的基本问题。铁调节蛋白（IRP）是哺乳动物铁代谢的关键调节因子，它结合靶mRNA中的铁响应元件（IRE），从而控制铁的摄取和代谢命运。至少有6种编码不同功能蛋白的mRNA在其5'非翻译区含有一个IRE，允许IRP1和IRP2对mRNA翻译的铁依赖性控制。IRP或IRP作用的mRNA靶点（如血红素形成酶红系5′氨基乙酰化合成酶（eALAS））的失调会导致人类和人类疾病的动物模型中的疾病。尽管IRP被认为是哺乳动物铁代谢的中心调节因子，并控制多种功能不同的蛋白质的合成，但关于IRP如何选择性地控制含有ire的mRNA的命运，人们知之甚少。我们建议通过阐明铁状态改变对缺乏IRP1或IRP2小鼠中含5' ire mRNA翻译的影响来确定每种IRP的个体作用。此外，我们假设IRP结合活性的协调诱导是适当调节肝铁储存和输出以支持足够的红细胞形成率所必需的。我们进一步假设，众所周知的肝脏抵抗缺铁的能力依赖于IRP的充分诱导。我们将通过确定铁缺乏对肝铁代谢和铁依赖功能的影响来检验这些假设。

DESCRIPTION (provided by applicant): This application is in response to NOT-OD-09-058, "NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications." Studies supported by the parent grant address fundamental questions concerning how iron homeostasis is regulated in mammals. Iron regulatory proteins (IRP) are critical regulators of mammalian iron metabolism that bind iron responsive elements (IRE) in target mRNA thereby controlling the uptake and metabolic fate of iron. At least six mRNA encoding proteins of diverse functions contain a single IRE in their 5' untranslated region allowing iron-dependent control of mRNA translation by IRP1 and IRP2. Dysregulation of IRP or the mRNA targets of IRP action, such as the heme formation enzyme erythroid 5'aminolevulinate synthase (eALAS), causes disease in humans and animal models of human disease. Although IRP are considered central regulators of mammalian iron metabolism and control the synthesis of proteins of widely differing function relatively little is known concerning how IRP selectively control the fate of IRE-containing mRNA. We propose to determine the individual roles of each IRP by elucidating the effect of altered iron status on the translation of 5'IRE-containing mRNA in mice lacking IRP1 or IRP2. Furthermore, we hypothesize that coordinate induction of IRP binding activity is required for the proper regulation of liver iron storage and export to support adequate rates of red cell formation. We further hypothesize that the well-known ability of liver to resist iron deficiency is dependent on adequate induction of IRP. We will test these hypotheses by determining the impact of iron deficiency on liver iron metabolism and on iron dependent functions. PUBLIC HEALTH RELEVANCE: Disorders of iron metabolism, whether caused by genetic errors, maladaptive response to disease, or diet are major public health issues affecting Americans. Iron regulatory proteins (IRPs) are critical components of a sensory and regulatory system that controls iron metabolism in key tissues including liver and their dysregulation of IRP action contributes to hematologic and neurologic diseases. This proposal focuses on elucidating the role of each IRP in the control of liver iron metabolism and function and its impact on the maintenance of whole body iron homeostasis.