权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9243242
负责人：
JANE-JANE CHEN
金额：
$ 33.93万
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 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243242
关键词：
Adult Affect Anemia BFU-E Basophilic Erythroblast Basophils Bone Marrow CD34 gene Cells Chronic Disease Clinical Development Disease Erythroblasts Erythrocytes Erythroid Erythropoiesis Etiology Fetal Hemoglobin Fetal Liver Gene Expression Genetic Translation Globin Heme Heme Iron Hemoglobin Hemoglobinopathies Human Incidence Infant Iron Iron deficiency anemia Knock-in Laboratories Lead Malignant Neoplasms Maps Mediating Mediator of activation protein Mendelian disorder Messenger RNA Methods Molecular Molecular Profiling Mus Outcome Outcome Study Oxidative Stress Pathway interactions Patients Phenotype Phosphorylation Phosphotransferases Process Production Pronormoblasts Proteins Regulation Research Ribosomes Role Severities Signal Transduction Sorting - Cell Movement Spleen Stress Technology Testing Thalassemia Time Transcriptional Regulation Translating Translational Regulation Translations biological adaptation to stress density embryonic stem cell erythroid differentiation genome-wide genome-wide analysis in vivo iron deficiency mouse model novel novel therapeutics progenitor public health relevance ribosome profiling

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective for 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 translational control by the heme-regulated eIF2� kinase (HRI) in oxidative stress and stress erythropoiesis. Our laboratory has demonstrated that HRI is necessary to reduce ineffective erythropoiesis and to maintain proper gene expression in erythroid precursors during iron deficiency. HRI is also essential for reducing the phenotypic severities of �-thalassemia. Phosphorylation of eIF2� by HRI not only inhibits translation globally, but also selectively increases the translation of ATF4 mRNA in primary erythroid precursors. This HRI-activated ATF4 stress response pathway is necessary to mitigate oxidative stress and to promote erythroid differentiation. Most recently, HRI-eIF2�P pathway has been shown to induce fetal hemoglobin (HbF) production in human CD34+ cells undergoing erythroid differentiation. While transcriptional regulation during erythropoiesis has been studied extensively, much less is known about the role of translational control in this process. We hypothesize that eIF2 �P-mediated translation is necessary to mitigate oxidative stress and to promote erythroid differentiation during stress erythropoiesis. We will employ a recently developed genome-wide approach, ribosome profiling, to study translational regulation during normal and stress erythropoiesis in heme deficiency and in �-thalassemia. A novel line of erythroid-specific eIF2�Ser51Ala knockin (erythroid- �A/A) mice, which are defective in eIF2�P signaling specifically in the erythroid lineage, will be generated. Erythroblasts isolated by FACS sorting from fetal livers of wild type (Wt), Hri-/- and erythroid-A/A mice under iron sufficient and deficint conditions, will be used to study the role of heme, HRI and eIF2�P in regulating in vivo translation genome-wide. In addition, ribosome profiling will also be performed in splenic basophilic erythroblasts of �-thalassemic mice. The outcomes of these proposed studies will elucidate the essential role of heme and eIF2�P-mediated translation in erythropoiesis under stress conditions. This proposed research will also uncover novel molecular mechanisms in translational regulation and new proteins produced in the erythroid lineage during differentiation. The novel information obtained from these studies will advance the field of erythropoiesis greatly and will have a very significant impact on the development of new therapies for hemoglobinopathies.

描述(由申请人提供)：我们对这项拟议研究的长期目标是帮助更全面地了解应激条件下和红细胞紊乱情况下血红蛋白合成和红细胞生成的调节。在这项建议中，我们重点关注在氧化应激和应激性红细胞生成中由血红素调节的eIF2�激酶(HRI)的翻译控制。我们的实验室已经证明，在缺铁期间，HRI对于减少无效的红细胞生成和维持红系前体细胞适当的基因表达是必要的。HRI对于降低�-地中海贫血的表型严重程度也是必不可少的。HRi对eIF2�的磷酸化不仅抑制整体翻译，而且选择性地增加原始红系前体中ATF4mRNA的翻译。这种HRI激活的ATF4应激反应通路对于减轻氧化应激和促进红系分化是必要的。最近的研究表明，hRI-eIF2CD34+细胞在红系分化过程中可以诱导胎儿血红蛋白(�)的产生。虽然红细胞生成过程中的转录调控已经得到了广泛的研究，但对翻译调控在这一过程中的作用却知之甚少。我们假设eIF2�P介导的翻译在应激性红细胞生成过程中对于减轻氧化应激和促进红系分化是必要的。我们将使用最近开发的全基因组方法，核糖体图谱，来研究血红素缺乏症和�地中海贫血患者正常和应激性红细胞生成过程中的翻译调节。将产生一种新的红系特异性eIF2�Ser51Ala敲门小鼠(Redid-�A/A)，它们在红系谱系中存在eIF2�P信号缺陷。用流式细胞仪分选野生型(Wt)胎肝、Hri-/-和红系A/A小鼠在铁充足和缺铁条件下的红细胞，研究血红素、Hri和eIF2�P在体内全基因组翻译调控中的作用。此外，还将在�地中海贫血小鼠的脾嗜碱性红细胞中进行核糖体分析。这些研究的结果将阐明血红素和eIF2�P介导的翻译在应激条件下的红细胞生成中的重要作用。这项拟议的研究还将揭示翻译调控的新分子机制和红系分化过程中产生的新蛋白质。从这些研究中获得的新信息将极大地促进红细胞生成领域的发展，并将对血红蛋白疾病的新疗法的开发产生非常重要的影响。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stress-enhanced translation of γ-globin mRNA.

γ-珠蛋白 mRNA 的应激增强翻译。

DOI：
10.1182/blood-2014-09-599290
发表时间：
2014
期刊：
Blood
影响因子：
20.3
作者：
Chen,Jane-Jane
通讯作者：
Chen,Jane-Jane

Translational control by heme-regulated elF2α kinase during erythropoiesis.

红血管调节的ELF2α激酶在红细胞生成过程中受到翻译控制。

DOI：
10.1097/moh.0000000000000704
发表时间：
2022-05-01
期刊：
CURRENT OPINION IN HEMATOLOGY
影响因子：
3.2
作者：
Chen, Jane-Jane;Zhang, Shuping
通讯作者：
Zhang, Shuping

Targeting elevated heme levels to treat a mouse model for Diamond-Blackfan Anemia.

DOI：
10.1016/j.exphem.2021.10.005
发表时间：
2022-01
期刊：
Experimental hematology
影响因子：
2.6
作者：
Sjögren SE;Chen J;Mattebo A;Alattar AG;Karlsson H;Siva K;Soneji S;Tedgård U;Chen JJ;Gram M;Flygare J
通讯作者：
Flygare J

Stressing HbF synthesis: role of translation?

强调 HbF 合成：翻译的作用？