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，我们重点关注翻译控制。我们的实验室已经证明，HRI 对于减少无效红细胞生成和维持正常红细胞生成是必要的。 HRI 导致红系前体细胞中的基因表达对于降低 β-地中海贫血的表型严重程度也至关重要。HRI 磷酸化不仅可以抑制整体翻译，还可以选择性地增加原代红系前体细胞中 ATF4 mRNA 的翻译。 HRI 激活的 ATF4 应激反应途径对于减轻氧化应激和促进红细胞分化是必要的。 HRI-eIF2�P 通路已被证明可诱导正在进行红细胞分化的人类 CD34+ 细胞产生胎儿血红蛋白 (HbF)，虽然红细胞生成过程中的转录调控已被广泛研究，但我们对翻译控制在此过程中的作用知之甚少。 eIF2·P介导的翻译对于减轻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，我们将采用最近开发的全基因组。方法，核糖体分析，研究血红素缺乏和β-地中海贫血的正常和应激红细胞生成过程中的翻译调节，一种新的红系特异性eIF2�Ser51Ala敲入（红系-�A/A）小鼠，其在eIF2中存在缺陷。将产生通过 FACS 分选从野生型胎儿肝脏中分离的红细胞谱系中的 P 信号传导。 (Wt)、铁充足和缺铁条件下的 Hri-/- 和 erythroid-A/A 小鼠将用于研究血红素、HRI 和 eIF2�P 在调节体内全基因组翻译中的作用。还将对地中海贫血小鼠的脾嗜碱性成红细胞进行分析，这些拟议研究的结果将阐明血红素和血红素的重要作用。应激条件下 eIF2�P 介导的红细胞生成翻译也将揭示翻译调节的新分子机制以及红细胞谱系在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推进红细胞生成领域的发展，并对血红蛋白病新疗法的开发产生非常重大的影响。

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）

Stressing HbF synthesis: role of translation?

强调 HbF 合成：翻译的作用？

DOI：
发表时间：
2013-07-25
期刊：
影响因子：
20.3
作者：
Chen, Jane;Perrine, Susan
通讯作者：
Perrine, Susan

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

以升高的血红素水平为目标来治疗戴蒙德-布莱克凡贫血小鼠模型。

DOI：
发表时间：
2022-01
期刊：
影响因子：
2.6
作者：
Sjögren, Sara E;Chen, Jun;Mattebo, Alexander;Alattar, Abdul G;Karlsson, Helena;Siva, Kavitha;Soneji, Shamit;Tedgård, Ulf;Chen, Jane;Gram, Magnus;Flygare, Johan
通讯作者：
Flygare, Johan

Translational control by heme-regulated elF2α kinase during erythropoiesis.

红细胞生成过程中血红素调节的 eF2α 激酶的翻译控制。

DOI：
发表时间：
2022-05-01
期刊：
影响因子：
3.2
作者：
Chen, Jane;Zhang, Shuping
通讯作者：
Zhang, Shuping

Bitopertin, a selective oral GLYT1 inhibitor, improves anemia in a mouse model of β-thalassemia.

Bitopertin 是一种选择性口服 GLYT1 抑制剂，可改善 β 地中海贫血小鼠模型的贫血。

DOI：
发表时间：
2019
期刊：
影响因子：
8
作者：
Matte, Alessandro;Federti, Enrica;Winter, Michael;Koerner, Annette;Harmeier, Anja;Mazer, Norman;Tomka, Tomas;Di Paolo, Maria Luisa;De Falco, Luigia;Andolfo, Immacolata;Beneduce, Elisabetta;Iolascon, Achille;Macias;Chen, Jane
通讯作者：
Chen, Jane

The heme-regulated inhibitor is a cytosolic sensor of protein misfolding that controls innate immune signaling.

血红素调节抑制剂是一种蛋白质错误折叠的胞质传感器，可控制先天免疫信号。

DOI：
发表时间：
2019-07-05
期刊：
影响因子：
0
作者：
Abdel;Carneiro, Leticia A M;Downey, Jeffrey;Tsalikis, Jessica;Outlioua, Ahmed;Prescott, Dave;Da Costa, Leandro Silva;Hovingh, Elise S;Farahvash, Armin;Gaudet, Ryan G;Molinaro, Raphael;van Dalen, Rob;Lau, Charles C Y;Azimi, Farshad
通讯作者：
Azimi, Farshad