Biological Functions of Iron Responsive Elements

铁反应元件的生物学功能

基本信息

批准号：
8544557
负责人：
Richard S. Eisenstein
金额：
$ 9万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2013-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8544557
关键词：
2-oxoglutarate 3-dioxygenase proline 5&apos Untranslated Regions Address Affect American Anemia Animal Model Biological Process Blood Carnitine Cell physiology Cells Characteristics Cognitive Cues Cultured Cells Development Diet Dietary Iron Disease Economics Elements Erythrocytes Erythropoiesis Erythropoietin Exhibits Ferritin Functional disorder Funding Gene Expression Profile Gene Mutation Gene Targeting Genes Genetic Genetic Translation Goals Health Hemoglobin Homeostasis Human Hydrolase Hypoxia Hypoxia Inducible Factor Individual Intestines Iron Iron Metabolism Disorders Iron Regulatory Protein 1 Iron deficiency anemia Iron-Regulatory Proteins Kidney Kidney Failure Knowledge Lead Life Cycle Stages Link Maintenance Malignant Neoplasms Mammals Messenger RNA Metabolic Metabolism Mitochondria Mus Muscle Neurologic Nitric Oxide Nutrient Nutritional Oncogenic Open Reading Frames Output Oxygen Pathway interactions Phosphorylation Physiological Polycythemia Polycythemia Vera Premature Birth Production Protein Binding Protein Biosynthesis Protein Isoforms Proteins Public Health RNA-Binding Proteins Regulation Regulatory Element Reticulocytosis Role SLC11A2 gene Sensory Serum Splenomegaly Sum Symptoms Time Tissues Up-Regulation Vertebrates Woman Work absorption bHLH-PAS factor HLF common treatment derepression gain of function genome-wide human disease iron (III) reductase iron deficiency iron metabolism kidney cell metal transporting protein 1 mutant normal aging novel novel therapeutics premature response sensor social transcription factor transcriptomics treatment strategy uptake

项目摘要

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 other symptoms observed in humans with HIF2¿ gain-of-function or in animal models of altered HIF2¿ regulation. Transcriptomic analysis of intestinal mucosal cells in IRP1-/- mice revealed up-regulation of multiple HIF2¿ gene targets suggesting enhanced iron absorption capacity as would be observed in hypoxia when HIF2¿ is activated. 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 with the level of expression and action of HIF2¿. We propose that the IRP1-HIF2¿ regulatory axis is required for the integration of iron and oxygen metabolism in mammals. Consequently, the specific aims are to: 1) determine the tissue-specific roles of IRP1-dependent regulation of HIF2¿ in the adaptive response to altered iron and oxygen status in mice; 2) determine the mechanisms regulating HIF2¿ mRNA translation by iron and oxygen and their impact on HIF2¿ action in erythropoietin-secreting human kidney cells. 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.

描述（由申请人提供）：铁代谢紊乱，无论是由先天性遗传错误、对疾病或饮食的适应不良反应引起的，都是美国和全世界的主要公共卫生问题。营养性铁缺乏与认知发育受损和工作减少有关。除了铁代谢本身之外，参与缺铁的适应性细胞和有机体反应的生理途径仍然不明确。除了饮食之外，贫血也可能是由氧传感途径紊乱引起的。联系肾衰竭、正常衰老、血红蛋白或其他蛋白质的基因突变，以及由于尚未完全转变为控制促红细胞生成素生成的产后机制而导致的早产。总而言之，这些病理状态影响着数百万人。仅在美国，正确整合铁和氧代谢的控制对于脊椎动物整个生命周期的最佳健康至关重要，铁调节蛋白 1 (IRP1) 和 IRP2 是细胞铁的中央调节因子。 IRP 决定了维持铁稳态和响应铁状态的适应性变化所需的 mRNA 编码蛋白的命运，编码缺氧诱导因子 2¿ (HIF2¿) 是全基因组对氧和铁反应的核心转录因子，之前已被证明是培养细胞中 IRP1 的特定靶标。 mRNA 翻译在 IRP1-/- 小鼠中被激活，但在 IRP1-/- 小鼠中没有被激活，其红细胞生成受到严重干扰，包括短暂的严重红细胞增多症，并表现出在患有 HIF2 的人类中观察到的其他症状。功能获得或在 HIF2 改变的动物模型中IRP1-/- 小鼠肠粘膜细胞的转录组分析揭示了多个 HIF2 的上调。基因靶标表明铁吸收能力增强，如在缺氧时观察到 HIF2¿我们迄今为止的结果还表明 HIF2 的 5' 非翻译区被激活。 mRNA 包含多个先前未被识别的假定翻译调控元件，这些元件强烈表明翻译控制是一个关键的附加水平，在该水平上铁和氧水平的变化与 HIF2 的表达和作用水平相结合。我们建议IRP1-HIF2¿调节轴是哺乳动物体内铁和氧代谢整合所必需的，具体目标是：1）确定 IRP1 依赖性 HIF2 调节的组织特异性作用。小鼠对铁和氧状态改变的适应性反应；2) 确定调节 HIF2 的机制铁和氧的 mRNA 翻译及其对 HIF2 的影响¿在分泌促红细胞生成素的人肾细胞中的作用阐明 IRP1-HIF2 的作用。我们的研究可能最终对开发治疗常见疾病的新治疗策略产生变革性影响。