Biological Functions of Iron Responsive Elements

描述（由申请人提供）：铁代谢紊乱，无论是由先天遗传错误、对疾病或饮食的不适应反应引起的，都是美国和全世界的主要公共卫生问题。营养缺铁与认知发育受损和工作产出减少有关，从而造成严重的负面经济和社会后果。除了铁代谢本身，参与适应性细胞和机体对铁缺乏反应的生理途径仍然不清楚。除了饮食外，与肾功能衰竭、正常衰老、血红蛋白或其他蛋白质的基因突变相关的氧感应通路紊乱，以及在未完全转换到控制红细胞生成素产生的产后机制时早产的结果，都可能引起贫血。总而言之，仅在美国，这些病态状态就影响着数百万人。适当整合铁和氧代谢控制的能力对于整个生命周期的最佳健康至关重要。在脊椎动物中，铁调节蛋白1 （IRP1）和IRP2是细胞铁代谢的主要调节因子。IRP决定了mRNA编码蛋白的命运，这些蛋白是维持铁稳态和对铁状态的适应性变化所必需的。低氧诱导因子2¿（HIF2¿）是基因组对氧和铁反应的核心转录因子，先前已被证明是培养细胞中IRP1的特异性靶标。我们证明了HIF2¿mRNA翻译在IRP1-/-小鼠中被激活，而在IRP2 -/-小鼠中没有被激活。IRP1 -/-小鼠有严重的红细胞生成障碍，包括短暂的严重红细胞增多症，并表现出应激性红细胞生成失调的症状。到目前为止，我们的研究结果还表明，HIF2¿mRNA的5'非翻译区包含多个先前未被识别的假定的翻译调控元件，这强烈表明翻译控制是一个关键的额外水平，在这个水平上，铁和氧水平的变化与HIF2¿的表达和作用水平相结合。我们提出IRP1-HIF2调控轴是协调铁吸收和其他适应过程与稳态和应激诱导的红细胞生成所必需的。因此，具体目的是确定：1)IRP1缺陷在红细胞增多症发展中的组织特异性作用；2)铁和氧调控HIF2¿mRNA翻译的机制。在阐明IRP1-HIF2¿轴在铁和氧代谢中枢通路的适应性和非适应性控制中的作用时，我们的研究可能最终对治疗常见疾病的新治疗策略的发展产生变革性影响。

DESCRIPTION (provided by applicant): Disorders of iron metabolism, whether caused by inborn genetic errors, maladaptive responses to disease or diet are major public health issues in the U.S. and throughout the world. Nutritional iron deficiency is associated with impaired cognitive development and reduced work output resulting in significant negative economic and social consequences. Other than iron metabolism per se, the physiological pathways involved in the adaptive cellular and organismal response to iron deficiency remain poorly defined. In addition to diet, anemia can be caused by disorders in oxygen sensing pathways associated with renal failure, normal aging, genetic mutations in hemoglobin or other proteins, and as a consequence of preterm delivery when the full switch to post-natal mechanisms of controlling erythropoietin production has not occurred. In sum, these pathological states affect millions of people in the U.S. alone. The ability to properly integrate the control of iron and oxygen metabolism is essential for optimal health throughout the life cycle. In vertebrates, iron regulatory protein 1 (IRP1) and IRP2 are central regulators of cellular iron metabolism. IRP dictate the fate of mRNA encoding proteins required for the maintenance of iron homeostasis and for the adaptive changes in response to iron status. The mRNA encoding hypoxia inducible factor 2¿ (HIF2¿), a transcription factor central to the genome wide responses to oxygen and iron, has been previously shown to be a specific target of IRP1 in cultured cells. We demonstrate that HIF2¿ mRNA translation is activated in IRP1-/- mice but not in IRP2 -/- mice. IRP1 -/- mice have profound disturbances in erythropoiesis, including a transient severe polycythemia, and display symptoms of dysregulated stress erythropoiesis. Our results to date also demonstrate that the 5' untranslated region of HIF2¿ mRNA contains multiple previously unrecognized putative translational regulatory elements that strongly suggest that translational control is a critical additional level at which changes in iron and oxygen level are integrated wit the level of expression and action of HIF2¿. We propose that the IRP1-HIF2¿ regulatory axis is required for coordinating iron absorption and other adaptive processes with homeostatic and stress-induced erythropoiesis. Consequently, the specific aims are to determine the: 1) tissue specific roles of IRP1 deficiency in the development of polycythemia; 2) mechanisms regulating HIF2¿ mRNA translation by iron and oxygen. In elucidating the role of the IRP1-HIF2¿ axis in the adaptive and maladaptive control of central pathways of iron and oxygen metabolism our studies may ultimately have a transformative effect on the development of new therapeutic strategies for treatment of common disorders.