FOXO3 Regulation of Normal and Stress Erythropoiesis

FOXO3 对正常和应激性红细胞生成的调节

基本信息

批准号：
9403199
负责人：
SAGHI GHAFFARI
金额：
$ 42.31万
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：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9403199
关键词：
Affect Anemia Anemia due to Chronic Disorder Apoptosis Apoptotic Bone Marrow CD34 gene CDC42 gene Cell Nucleus Cells Chronic Chronic stress Clinical Disease Ectopic Expression Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis FOXO3A gene Family member Functional disorder Gene Cluster Genes Genetic Genetic Diseases Genomics Goals Guanosine Triphosphate Phosphohydrolases Health Hemoglobinopathies Human In Vitro Knowledge Mediating Mediator of activation protein Methodology Mitochondria Modeling Mus Nuclear Oxidation-Reduction Oxidative Stress Pathway interactions Pattern Physiological Physiological Processes Polycythemia Vera Population Process Production Property Publishing Regulation Role Side Spleen Stress Testing Therapeutic base beta Thalassemia biological adaptation to stress cell motility design gain of function improved mouse model novel organelle movement quantitative imaging response rho GTP-Binding Proteins transcription factor

Affect Anemia Anemia due to Chronic Disorder Apoptosis Apoptotic Bone Marrow CD34 gene CDC42 gene Cell Nucleus Cells Chronic Chronic stress Clinical Disease Ectopic Expression Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis FOXO3A gene Family member Functional disorder Gene Cluster Genes Genetic Genetic Diseases Genomics Goals Guanosine Triphosphate Phosphohydrolases Health Hemoglobinopathies Human In Vitro Knowledge Mediating Mediator of activation protein Methodology Mitochondria Modeling Mus Nuclear Oxidation-Reduction Oxidative Stress Pathway interactions Pattern Physiological Physiological Processes Polycythemia Vera Population Process Production Property Publishing Regulation Role Side Spleen Stress Testing Therapeutic base beta Thalassemia biological adaptation to stress cell motility design gain of function improved mouse model novel organelle movement quantitative imaging response rho GTP-Binding Proteins transcription factor

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项目摘要

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.

概括慢性氧化应激加剧了包括血红蛋白病在内的一系列红细胞疾病，炎症的多性炎症和贫血；然而，红细胞慢性应激所涉及的机制响应仍然相对出乎意料。此外，它们对正常身体过程的影响是未知。我们的重点一直放在体内稳态转录因子FOXO3上，这对于红细胞生成氧化还原状态的调节。我们最近表明FOXO3对于终端至关重要红细胞生成的成熟和枚举。另一方面，我们的研究表明失去 FOXO3在β-丘脑贫血模型中显着改善了贫血，这是红斑的遗传疾病氧化还原不平衡的细胞以其核心。鉴于FOXO3功能的广泛范围，其影响的程度关于红细胞生成可能取决于上下文。我们的总体目标是检验慢性的假设 FOXO3介导的应力响应途径的激活对有害的贡献显着贡献红细胞疾病的病理生理。为了检验这一假设，我们建议员工新颖的定量成像方法，基因组高通量方法和人类红细胞的体外培养以及在纯遗传背景上产生的小鼠模型以及功能损失和功能获得实现以下独立但高度互补和协同目的的方法：（目标1）：调查FOXO3调节成红细胞含糖的机制；（目标2）：阐明FOXO3在β-丘脑血症红细胞生成中的作用。这些合并的研究将阐明慢性激活FOXO3介导的压力反应如何改变正常的生理过程和特异性，更广泛的红细胞性疾病加剧了β-硫代助理。