FOXO3 Regulation of Normal and Stress Erythropoiesis

总结 慢性氧化应激会加剧一系列红系疾病，包括血红蛋白病， 真性红细胞增多症和炎症性贫血;然而红细胞慢性应激的机制- 反应仍然相对未探索。此外，它们对正常生理过程的影响是 未知我们的重点一直是稳态转录因子FOXO 3，这是必不可少的， 红细胞生成氧化还原状态的调节。我们最近发现FOXO 3对终末细胞的生长至关重要， 成熟和去核。另一方面，我们的研究表明， FOXO 3显著改善红系遗传性疾病β-地中海贫血模型中的贫血 核心是氧化还原失衡的细胞。考虑到FOXO 3功能的广泛范围，其影响的程度 红细胞生成可能取决于上下文。我们的首要目标是检验慢性病 FOXO 3介导的应激反应途径的激活显著促进了有害的 红细胞疾病的病理生理学。为了验证这一假设，我们建议采用新的定量 成像方法学、基因组高通量方法和人成红细胞的体外培养 以及在纯遗传背景下结合功能丧失和获得的小鼠模型 采取各种办法，以实现下列独立但又高度互补和协同的目标：（目标1）： 研究FOXO 3调节成红细胞去核的机制;（目的2）： 阐明FOXO 3在β地中海贫血红细胞生成中的作用。这些综合研究将阐明 慢性激活FOXO 3介导的应激反应如何改变正常的生理过程， 具体地和更广泛地加重β-地中海贫血的红系疾病。

SUMMARY Chronic oxidative stress exacerbates an array of erythroid disorders, including hemoglobinopathies, polycythemia vera and anemia of inflammation; yet the mechanisms engaged by erythroid chronic stress- response remain relatively unexplored. In addition, their impact on normal physiological processes is unknown. Our focus has been on the homeostatic transcription factor FOXO3 which is essential for the regulation of the erythropoiesis redox state. We showed recently that FOXO3 is critical for terminal maturation and enucleation in erythropoiesis. On the other hand, our studies indicate that the loss of FOXO3 improves significantly anemia in a model of ß-thalassemia that is a genetic disorder of erythroid cells with redox imbalance at its core. Given the broad scope of FOXO3 functions, the extent of its impact on erythropoiesis may depend on the context. Our overarching goal is to test the hypothesis that chronic activation of FOXO3-mediated stress-response pathways contributes significantly to the deleterious pathophysiology of erythroid disorders. To test this hypothesis we propose to employ novel quantitative imaging methodologies, genomic high-throughput approaches, and in vitro cultures of human erythroblasts and mouse models generated on pure genetic background combined with loss- and gain-of-function approaches to achieve the following independent yet highly complementary and synergistic aims: (Aim 1): To investigate mechanisms whereby FOXO3 regulates erythroblast enucleation; (Aim 2): To elucidate the role of FOXO3 in β-thalassemic erythropoiesis. These combined studies will elucidate how chronic activation FOXO3-mediated stress response may alter normal physiological processes and aggravate β-thalassemia specifically and more broadly erythroid disorders.