AKT Signaling and Oxidative Stress Regulation of Erythropoiesis

红系细胞的日常生产需要红系细胞分裂和成熟的紧密协调。 细胞和对需要应激性红细胞生成的临床条件的即时反应。成熟 红系祖细胞和早期红系母细胞(红系前体)高度增殖，而增殖 在后期急剧下降。阐明调节红系细胞分化的分子途径 成熟对于设计针对一些红系疾病的靶向治疗是至关重要的，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 促红细胞生成素受体(EPOR)是由JAK2酪氨酸激酶介导的，对其受体来说是必不可少的。 红系细胞发育正常。尽管EPOR信号在红系调节中的作用 存活和细胞分裂已经被广泛地表征，EPOR信号对 红系细胞分化和成熟的转录程序还不是很清楚。尤其是，不 关于协调红系前体细胞分裂、细胞周期退出、 分化和成熟。我们实验室的证据表明，AKT丝氨酸苏氨酸蛋白 激酶在红系细胞分裂和成熟调控中的重要作用 EPOR信令。我们已经确定了AKT对GATA-1和FOXO_3转录因子和mTOR的调节 对于协调红系细胞分裂和成熟来说，激活剂是至关重要的。此外，我们的研究还支持 AKT靶标FOXO_3对生理活性氧物种(ROS)的调节作用 在红系细胞成熟中的作用。ROS被认为在许多红系疾病中起关键作用，包括在 --地中海贫血型红细胞生成。因此，我们提出了一个模型，在该模型中，AKT下游的信号，特别是 FOXO_3、mTOR和GATA-1协调红系前体细胞分裂和成熟 协调至少部分是由ROS调节的。为了研究这一模型的有效性，我们提出了 目标1：研究FOXO_3在应激性红细胞生成反应中的作用；目标2： 阐明野生型和FOXO_3基因缺失小鼠红系细胞增殖的分子机制 探讨AKT对GATA-1的调控机制。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FOXO_3在？-中的势函数。 地中海贫血。这些研究的结果将提供关于调节机制的关键信息 红系细胞的分裂和成熟，并应阐明红血球生成的基本方面。

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.