HRI-eIF2a Phosphorylation Signaling in Oxidative Stress and Erythropoiesis

氧化应激和红细胞生成中的 HRI-eIF2a 磷酸化信号传导

基本信息

批准号：
7863731
负责人：
JANE-JANE CHEN
金额：
$ 25.2万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-12 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7863731
关键词：
Ablation Affect Age Alleles Anemia Apoptosis Applications Grants Basophilic Erythroblast Cells Chronic Chronic Disease Clinical Development Diabetes Mellitus Differentiation and Growth Disease Erythrocytes Erythroid Erythroid Cells Erythropoiesis Erythropoietic Protoporphyria Etiology Family Fetal Liver Gene Expression Globin Heme Heme Iron Hemoglobin Hemoglobinopathies Incidence Infant Inflammation Iron Iron deficiency anemia Laboratories Lead Malignant Neoplasms Mediating Messenger RNA Modeling Molecular Mus Outcome Outcome Study Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Population Proteins Reactive Oxygen Species Regulation Reporting Research Role Severities Signal Pathway Signal Transduction Sorting - Cell Movement Source Staging Stress Thalassemia Translations biological adaptation to stress endoplasmic reticulum stress erythroid differentiation in vivo insight member mouse model mutant novel progenitor public health relevance

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective of this proposed research is to contribute to the more comprehensive understanding of the regulation of hemoglobin synthesis and erythropoiesis under stress conditions and in red cell disorders. In this proposal, we focus on the role of the heme-regulated eIF21 kinase (HRI) signaling pathway in oxidative stress and stress erythropoiesis of chronic iron deficiency and ?-thalassemia. Our laboratory has demonstrated that HRI is necessary to reduce ineffective erythropoiesis and to maintain proper gene expression in erythroid precursors during iron deficiency, in addition to translational control of globin synthesis. HRI is also essential for reducing the phenotypic severities of ?-thalassemia. Recently, we uncovered a novel role of HRI in erythroid differentiation during iron deficiency anemia and in 2-thalassemia. Additionally, HRI also induces the ATF4 stress response pathway upon oxidative stress in the erythroid lineage to mitigate levels of reactive oxygen species (ROS) and apoptosis. We hypothesize that the HRI mediated eIF21P-ATF4 stress response pathway is necessary to reduce oxidative stress and to promote erythroid differentiation during stress erythropoiesis. We will investigate this hypothesis using in vivo stress models of ?- thalassemia and iron deficiency anemia. The signaling pathway will be delineated using erythroid specific ablation of eIF21 phosphorylation and ATF4-/- mouse models. Ineffective erythropoiesis that occurs in ?- thalassemia is the source of major complications in this disease and other red cell disorders with hemoglobinopathy. Results from our proposed studies should further advance our understanding of the molecular mechanism of ineffective erythropoiesis and the functions of HRI in the growth and differentiation of erythroid cells under stress conditions and in disease states. The outcome of this proposed study might also lead to potential application of HRI and its signaling pathway in treating thalassemia and other red cell diseases. Anemia is also prevalent in patients with chronic inflammations, cancers, and diabetes as well as upon aging. The outcome of these proposed studies might also provide insights into these anemias. PUBLIC HEALTH RELEVANCE: The purpose of this proposed research is to further our understanding of the molecular mechanisms of ineffective red blood cell development in anemias of iron deficiency and ?-thalassemia. The outcome of this study may lead to the discovery of novel drug treatment for red blood cell diseases.

描述（由申请人提供）：我们这项拟议研究的长期目标是有助于更全面地了解应激条件下和红细胞疾病中血红蛋白合成和红细胞生成的调节。在本提案中，我们重点关注血红素调节的 eIF21 激酶 (HRI) 信号通路在慢性缺铁和β-地中海贫血的氧化应激和应激性红细胞生成中的作用。我们的实验室已经证明，除了球蛋白合成的翻译控制之外，HRI 对于减少无效的红细胞生成和缺铁期间维持红细胞前体中适当的基因表达是必要的。 HRI 对于降低 β 地中海贫血的表型严重程度也至关重要。最近，我们发现了 HRI 在缺铁性贫血和 2-地中海贫血期间红细胞分化中的新作用。此外，HRI 还在红系谱系中的氧化应激时诱导 ATF4 应激反应途径，以减轻活性氧 (ROS) 水平和细胞凋亡。我们假设 HRI 介导的 eIF21P-ATF4 应激反应途径对于减少氧化应激和在应激红细胞生成过程中促进红细胞分化是必要的。我们将使用β-地中海贫血和缺铁性贫血的体内应激模型来研究这一假设。将使用 eIF21 磷酸化的红系特异性消融和 ATF4-/- 小鼠模型来描绘信号通路。 β-地中海贫血中发生的无效红细胞生成是该疾病和其他伴有血红蛋白病的红细胞疾病的主要并发症的根源。我们提出的研究结果应进一步加深我们对无效红细胞生成的分子机制以及 HRI 在应激条件和疾病状态下红细胞生长和分化中的功能的理解。这项研究的结果也可能导致 HRI 及其信号通路在治疗地中海贫血和其他红细胞疾病中的潜在应用。贫血在患有慢性炎症、癌症、糖尿病以及衰老的患者中也很常见。这些拟议研究的结果也可能提供对这些贫血的见解。公共健康相关性：这项研究的目的是进一步了解缺铁性贫血和β-地中海贫血中红细胞发育不良的分子机制。这项研究的结果可能会导致发现治疗红细胞疾病的新药物。