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Biological Functions of Iron Responsive Elements

铁反应元件的生物学功能

基本信息

批准号：
8737225
负责人：
Richard S. Eisenstein
金额：
$ 33.62万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737225
关键词：
2-oxoglutarate 3-dioxygenase proline 5&apos Untranslated Regions Address Affect American Anemia Biological Process Cell physiology Cells Characteristics Chronic Kidney Failure Cognitive Cues Cultured Cells Development Diet Disease Economics Elements Ensure Erythrocytes Erythropoiesis Erythropoietin Exhibits Extramedullary Ferritin Functional disorder Funding Gene Expression Profile Gene Mutation Genes Genetic Genetic Translation Goals Health Hemoglobin Homeostasis Hydrolase Hypoxia Individual Inflammation Intestines Iron Iron Metabolism Disorders Iron Regulatory Protein 1 Iron-Regulatory Proteins Kidney Kidney Failure Knowledge Lead Life Cycle Stages Link Maintenance Malignant Neoplasms Messenger RNA Metabolic Metabolism Mus Nature Neurologic Nitric Oxide Nutrient Nutritional Oncogenic Open Reading Frames Output Oxygen Participant Pathway interactions Phosphorylation Physiological Polycythemia Polycythemia Vera Premature Birth Process Production Protein Binding Protein Biosynthesis Protein Isoforms Proteins Public Health Publishing RNA-Binding Proteins Regulation Regulatory Element Role SLC11A2 gene Sensory Serum Signal Transduction Splenomegaly Stress Sum Symptoms Time Tissues Vertebrates Wit Work absorption bHLH-PAS factor HLF common treatment derepression genome-wide human disease iron (III) reductase iron deficiency iron metabolism metal transporting protein 1 mutant normal aging novel novel therapeutics public health relevance response sensor social transcription factor 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 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.

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。营养性缺铁与认知发育受损和工作量减少有关，导致严重的负面经济和社会后果。除了铁代谢本身之外，参与适应性细胞和生物体对铁缺乏的反应的生理途径仍然不清楚。除饮食外，贫血还可由与肾衰竭、正常衰老、血红蛋白或其他蛋白质的基因突变相关的氧传感通路中的障碍引起，以及当控制促红细胞生成素产生的出生后机制的完全转换尚未发生时早产的结果。总之，这些病理状态仅在美国就影响了数百万人。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（IRP 1）和IRP 2是细胞铁代谢的中心调节因子。IRP决定了mRNA编码蛋白质的命运，这些蛋白质是维持铁稳态和响应铁状态的适应性变化所必需的。编码缺氧诱导因子2 <$$>（HIF 2 <$）的mRNA是一种对氧和铁的全基因组反应至关重要的转录因子，先前已被证明是培养细胞中IRP 1的特异性靶点。我们证明，HIF 2 <$mRNA翻译在IRP 1-/-小鼠中被激活，但在IRP 2-/-小鼠中没有。IRP 1-/-小鼠在红细胞生成中具有严重的紊乱，包括短暂的严重红细胞增多症，并显示应激性红细胞生成失调的症状。我们的研究结果还表明，HIF 2 <$mRNA的5'非翻译区含有多个以前未被识别的推定的翻译调控元件，这强烈表明，翻译控制是一个关键的额外水平，在该水平上，铁和氧水平的变化与HIF 2 <$的表达和作用水平相结合。我们认为IRP 1-HIF 2 <$调节轴是协调铁吸收和其他适应性过程与稳态和应激诱导的红细胞生成所必需的。因此，具体目标是确定：1）IRP 1缺乏在红细胞增多症发展中的组织特异性作用; 2）铁和氧调节HIF 2？mRNA翻译的机制。在阐明IRP 1-HIF 2 <$轴在铁和氧代谢的中枢途径的适应性和适应不良控制中的作用时，我们的研究最终可能对治疗常见疾病的新治疗策略的开发产生变革性影响。