Biological Function of Iron Responsive Elements

描述（由申请人提供）：本申请是对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。“由母基金支持的研究解决了有关哺乳动物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，它与靶mRNA中的铁反应元件（IRE）结合，从而控制铁的摄取和代谢。至少有六种不同功能的mRNA编码蛋白在其5'非翻译区含有一个IRE，允许IRP 1和IRP 2对mRNA翻译进行铁依赖性控制。IRP或IRP作用的mRNA靶标（例如血红素形成酶红系5 '氨基乙酰丙酸合酶（eALAS））的失调导致人类和人类疾病的动物模型中的疾病。虽然IRP被认为是哺乳动物铁代谢的中心调节因子，并控制功能差异很大的蛋白质的合成，但关于IRP如何选择性地控制含IRE的mRNA的命运却知之甚少。我们建议通过阐明铁状态改变对缺乏IRP 1或IRP 2的小鼠中含5 'IRE的mRNA翻译的影响来确定每个IRP的单独作用。此外，我们假设，协调诱导IRP结合活性是必要的适当调节肝脏铁储存和出口，以支持足够的红细胞形成率。我们进一步假设，众所周知的肝脏抵抗铁缺乏的能力是依赖于充分诱导IRP。我们将通过确定铁缺乏对肝脏铁代谢和铁依赖功能的影响来验证这些假设。 公共卫生相关性：铁代谢紊乱，无论是由遗传错误，对疾病的适应不良反应，还是饮食引起的，都是影响美国人的主要公共卫生问题。铁调节蛋白（IRP）是控制包括肝脏在内的关键组织中的铁代谢的感觉和调节系统的关键组分，并且IRP作用的失调有助于血液学和神经系统疾病。该建议的重点是阐明每个IRP在控制肝脏铁代谢和功能中的作用及其对维持全身铁稳态的影响。

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.