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AKT Signaling and Oxidative Stress Regulation of Erythropoiesis

AKT 信号传导和红细胞生成的氧化应激调节

基本信息

批准号：
8470631
负责人：
SAGHI GHAFFARI
金额：
$ 34.87万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470631
关键词：
3-Phosphoinositide Dependent Protein Kinase-1 AKT Signaling Pathway Acute Erythroblastic Leukemia Address Anemia Binding Cell Cycle Cell Differentiation process Cell Maturation Cell Proliferation Cell division Cells Chemicals Clinical Data Development Disease Drug Metabolic Detoxication Equilibrium Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythroid Progenitor Cells Erythropoiesis Erythropoietin Erythropoietin Receptor Functional disorder Gene Expression Regulation Goals JAK2 gene Knockout Mice Laboratories Light Longevity Mediating Modeling Molecular Mus Oxidative Stress Pathway interactions Phenylhydrazines Phosphotransferases Physiological Play Polycythemia Vera Production Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Publishing RNA Interference Reactive Oxygen Species Receptor Signaling Regulation Role Serine Signal Pathway Signal Transduction Staging Stress Thalassemia Threonine Wild Type Mouse base human FRAP1 protein human GATA1 protein inhibitor/antagonist insight irradiation mTOR Inhibitor new therapeutic target phenylhydrazine progenitor programs receptor research study response tool transcription factor

项目摘要

A tight coordination of erythroid cell division and maturation is required for daily production of erythroid cells and for immediate response to clinical conditions in which stress erythropoiesis is in demand. Mature erythroid progenitors and early erythroblasts (erythroid precursors) are highly proliferative, while proliferation decreases sharply in later stages. Elucidating molecular pathways that regulate erythroid cell differentiation and maturation is critical for devising targeted treatments for a number of erythroid disorders including erythroleukemias, thalassemias, and polycythemia vera. Signals generated from Erythropoietin (Epo) binding to its receptor erythropoietin receptor (EpoR) are mediated by JAK2 tyrosine kinase and are essential for normal erythroid cell development. Although the function of EpoR signaling in the regulation of erythroid survival and cell division has been characterized extensively, the impact of EpoR signaling on the transcriptional program of erythroid cell differentiation and maturation is less well understood. Particularly, not much is known about molecular mechanisms that coordinate erythroid precursor cell division, cell cycle exit, and differentiation and maturation. Evidence from our laboratory suggests that AKT serine threonine protein kinase mediates significant functions in the regulation of erythroid cell division and maturation downstream of EpoR signaling. We have identified AKT regulation of GATA-1 and FoxO3 transcription factors and mTOR kinase as critical for coordination of erythroid cell division and maturation. In addition our studies support the notion that regulation of physiological reactive oxygen species (ROS) by AKT target FoxO3 plays a significant role in erythroid cell maturation. ROS is thought to play a critical role in many erythroid disorders including in ¿-thalassemic erythropoiesis. Thus we propose a model in which signals downstream of AKT, specifically FoxO3, mTOR and GATA-1 coordinate erythroid precursor cell division and maturation and that this coordination is mediated at least in part by ROS. To investigate the validity of this model we propose the following aims: Aim 1: To investigate the role of FoxO3 in response to stress erythropoiesis; Aim 2: To elucidate the molecular mechanisms of erythroid cell proliferation in wild type and FoxO3 null mice; To investigate the mechanisms of AKT regulation of GATA-1. In these experiments we will evaluate the contribution of ROS and the role of mTOR. Finally we will examine the potential function of FoxO3 in ¿- thalassemia. Results from these studies will provide critical information on mechanisms of regulation of erythroid cell division and maturation, and should shed light on fundamental aspects of erythropoiesis.

红细胞的日常生产需要红细胞分裂和成熟的紧密协调细胞以及对需要应激性红细胞生成的临床状况立即做出反应。成熟红系祖细胞和早期有红细胞（红系前体）具有高度增殖性，而增殖后期急剧下降。阐明调节红细胞分化的分子途径成熟对于设计针对许多红细胞疾病的靶向治疗至关重要，包括红白血病、地中海贫血和真性红细胞增多症。促红细胞生成素 (Epo) 结合产生的信号其受体促红细胞生成素受体 (EpoR) 由 JAK2 酪氨酸激酶介导，对于红细胞发育正常。尽管 EpoR 信号在红细胞调节中的作用存活和细胞分裂已被广泛表征，EpoR 信号传导对细胞的影响红细胞分化和成熟的转录程序尚不清楚。特别是，不关于协调红系前体细胞分裂、细胞周期退出、以及分化和成熟。我们实验室的证据表明 AKT 丝氨酸苏氨酸蛋白激酶介导调节红系细胞分裂和下游成熟的重要功能 EpoR 信号传导。我们已经确定了 AKT 对 GATA-1 和 FoxO3 转录因子以及 mTOR 的调节激酶对于协调红细胞分裂和成熟至关重要。此外，我们的研究支持 AKT 靶标 FoxO3 对生理活性氧 (ROS) 的调节起着重要作用红细胞成熟中的作用。 ROS被认为在许多红细胞疾病中发挥着关键作用，包括 ¿-地中海贫血性红细胞生成。因此，我们提出了一个模型，其中 AKT 下游信号，特别是 FoxO3、mTOR 和 GATA-1 协调红系前体细胞分裂和成熟，并且这协调至少部分是由 ROS 介导的。为了研究该模型的有效性，我们提出以下目标：目标 1：研究 FoxO3 在应激性红细胞生成反应中的作用；目标 2：阐明野生型和 FoxO3 缺失小鼠红系细胞增殖的分子机制；到研究 AKT 对 GATA-1 的调节机制。在这些实验中，我们将评估 ROS 的贡献和 mTOR 的作用。最后我们将研究 FoxO3 在 ¿- 中的潜在功能地中海贫血。这些研究的结果将提供有关调节机制的关键信息红细胞分裂和成熟，并应阐明红细胞生成的基本方面。