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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：
8632381
负责人：
Richard S. Eisenstein
金额：
$ 34.34万
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/8632381
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 Hypoxia Inducible Factor 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

Project Summary: 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 with 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.

项目概述：铁代谢紊乱，是否由先天遗传错误、不适应所致